REVIEW CPD

Diagnosis and management of

Maeve P. Smith MB ChB MD

n Cite as: CMAJ 2017 June 19;189:E828-35. doi: 10.1503/cmaj.160830

ronchiectasis is a chronic, debilitating respiratory condition that affects people of all ages. It is most prevalent in KEY POINTS women and those older than 60 years, and prevalence is • Following a diagnosis of bronchiectasis, it is important to Bincreasing.1 Patients have daily excessive and associated investigate for an underlying cause. symptoms, recurrent chest infections and impaired health-related • Goals of management are to suppress airway infection and quality of life.2,3 In North America, management guidelines are lack- inflammation, to improve symptoms and health-related quality ing. This review discusses best evidence to guide the long-term of life. management of non–cystic fibrosis bronchiectasis in adults, focus- • There are now validated scoring tools to help assess disease ing on the two most common single-entity types of bronchiectasis severity, which can help to stratify management. in adults: idiopathic and postinfectious bronchiectasis4,5 (Box 1). • Good evidence supports the use of both exercise training and Table 1 lists all the types of bronchiectasis by cause. long-term macrolide therapy in long-term disease management.

What are the clinical features of bronchiectasis? has better sensitivity but may involve greater radiation doses. Typically, thin section (< 1 mm) slices acquired using a high- First described by Laennec in 1819, bronchiectasis refers to abnor- spatial frequency reconstruction algorithm should be used.18,19 mal permanently dilated airways, which are typically described as cylindrical, varicose or cystic in appearance.10,11 The condition is Determining underlying cause characterized by a vicious cycle of persistent bacterial infection and Determination of the underlying cause may alter management in excessive neutrophilic inflammation owing to impairment of airway as many as 37% of adults presenting with bronchiectasis.5 Rele- defence mechanisms. Risk factors for bronchiectasis are related vant diagnostic investigations for the most common causes are mainly to cause of the disease, with prevalence higher in patients described in Table 1.4–9 with autoimmune or connective tissue diseases,5 chronic infections such as HIV12 and chronic disease such as chronic obstructive Determining disease severity, presence of infection and pulmonary disease13 and asthma.14 Both rhinosinusitis and gastro- risk of progression esophageal reflux are also common among patients with bronchiec- Pertinent diagnostic investigations that may help to inform dis- tasis.5,15 The typical presenting clinical features are detailed in Box ease severity include lung function and analysis of sputum for 2.2,16 The most common symptom that should prompt suspicion of a bacterial, mycobacterial and fungal culture. diagnosis of bronchiectasis is a persistent cough productive of Cohort studies have found that in 64% to 79% of patients, there mucopurulent or purulent sputum.2,16 is evidence of persistent bacterial infection in the airways, even when patients are clinically stable.20,21 It is well established that in How is bronchiectasis diagnosed? the airways, as bacterial burden increases, so too does inflamma-

In patients presenting with clinical features suggestive of bronchiec- Box 1: Evidence used in this review tasis, appropriate baseline investigations include a chest radiograph, lung function tests (forced expiratory volume in the first second The evidence used in this review was obtained from a search of PubMed for articles published in English between January 2005 and [FEV ], forced vital capacity [FVC], lung volumes and diffusion capac- 1 March 2016. The medical subject headings “bronchiectasis” and 2 ity) and sputum bacteriological culture. These provide useful infor- “non–cystic fibrosis bronchiectasis” were used, in combination with mation for diagnostic triage and surveillance, although they lack the following keywords: “physiotherapy,” “exercise,” “macrolide,” specificity and sensitivity to the actual diagnosis of bronchiectasis.17 “anti-inflammatory,” “mucolytic,” “mucoactive,” “bronchodilator,” “corticosteroid,” “antibiotic,” “surgery,” and “transplant.” In addition, relevant papers retrieved from the reference lists of selected articles Confirming the diagnosis were reviewed. Clinical trials in adults with the highest level of The gold standard for confirming the diagnosis is high-resolution evidence for each section discussed were included, as well as computed tomography scan of the chest, ideally done when the observational studies when no controlled trials were available. patient is clinically stable.17 Volumetric computed tomography

E828 CMAJ | JUNE 19, 2017 | VOLUME 189 | ISSUE 24 © 2017 Joule Inc. or its licensors REVIEW - E829 The clinical The clinical 30 -antitrypsin level; phenotyping 1 Diagnostic investigations Diagnostic Serum alpha in those with low serum levels serum in those with low Sweat chloride assessment; CFTR genetic chloride assessment; CFTR genetic Sweat analysis as per guidelines (specialist referral) centre Measurement of nasal nitric oxide levels; of nasal nitric oxide Measurement centre epithelial biopsy (specialist ciliated referral) Total IgE > 500 IU/mL; positive A. positive IgE > 500 IU/mL; Total –specific IgE or immediate fumigatus on skin-prick testing reaction Rheumatoid factor; anti-CCP; other other anti-CCP; factor; Rheumatoid suspected pertinent to investigations review clinical diagnosis from Specialist gastrointestinal review; positive positive review; gastrointestinal Specialist on colonoscopy features pathological Typically diagnosed on chest CT diagnosed on chest Typically Various modalities available: video modalities available: Various upper study; swallow fluoroscopic ambulatory endoscopy; gastrointestinal manometry; pH studies; esophageal of swallow evaluation endoscopic flexible Serum immunoglobulins levels (IgG, IgA to and IgM); specific antibody responses Haemophilus influenzae pneuomococcal, antigens B and tetanus Other causes excluded Other causes This study also found a significant correlationalso found a significant This study

30 ISSUE 24 ISSUE | and patient-perceived cough severity. cough and patient-perceived 1 Mycobacterium Mycobacterium The natural history of bronchiectasis is variable. Some of bronchiectasis is variable. Some The natural history between such diverse bacterial community and clinical parame- community and clinical diverse bacterial between such ters as FEV than 140 species were identified in addition to the traditional spe- traditional the to addition in identified were species 140 than above. cies listed application and implication of the results of such alternative diag- results of such alternative and implication of the application established. have yet to be fully nostic methods dis no with year, per infections chest few a only have patients time, while others have more frequent, ease progression over to episodes, and progress more quickly prolonged infective an associated increase in risk of death. respiratory failure, with at may help to identify which patients are Clinical features that progression have not yet been formally higher risk of disease continues to focus on limiting further studied and management VOLUME 189 VOLUME |

22,23 Staphy- Less fre- 24,25 tuberculous Supporting diagnostic features Supporting diagnostic 21,26,27 JUNE 19, 2017 | CMAJ Evidence of emphysema; obstructive pattern on pattern of emphysema; obstructive Evidence spirometry; panniculitis Younger age (< 45 yr); history of malabsorption; history history of malabsorption; (< 45 yr); history age Younger of Pseudomonas aeruginosa history of pancreatitis; infection, aureus Staphylococcus infection, of male history infection; mycobacterial nontuberculous infertility History of chronic upper problems, problems, tract upper respiratory of chronic History abnormal ciliary media, male infertility; beat otitis on nasal brushings ± frequency pattern History of asthma; peripheral blood eosinophils > 500 peripheral of asthma; History IgG or positive fumigatus Aspergillus μL; positive cells/ fleeting of A. fumigatus; sputum culture precipitins; proximal chest; or CT radiograph on chest infiltrates scan chest on CT bronchiectasis History or clinical signs of connective tissue disease ± tissue disease signs of connective or clinical History vasculitis History or clinical signs of ulcerative colitis or Crohn or Crohn colitis signs of ulcerative or clinical History disease Williams–Campbell syndrome (); (bronchomalacia); Williams–Campbell syndrome and () syndrome Mounier-Kuhn lung sequestration History of reflux; history of aspiration history of reflux; History History of recurrent infections of recurrent History History or radiologic evidence of previous infection (e.g., infection of previous evidence or radiologic History , pertussis pneumonia, Bordetella frequently, mycobacteria) , nontuberculous tuberculosis excluded Other causes 4–9 , Streptococcus pneumoniae Mean Mean incidence 0.6%–2.7% 0.9%–7.8% 1.0%–3.0% 0.2%–0.6% 0.6%–11.3% 2.0%–10.3% 1.8%–31.1% 0.2%–11.3% 1.1%–16.0% 29.0%–42.0% 26.0%–53.0% Recent research using methods other than stan- Recent research using 28,29 , Moraxella catarrhalis -antitrypsin 1 The most common infecting pathogens are Haemophilus influ- The most common infecting deficiency Note: CCP = cyclic citrullinated peptide; CFTR = cystic fibrosis transmembrane conductance regulator; CT = computed tomography, Ig = immunoglobulin, SLE = systemic lupus erythematosus. lupus erythematosus. Ig = immunoglobulin, SLE = systemic tomography, = computed CT regulator; conductance transmembrane fibrosis CFTR = cystic peptide; = cyclic citrullinated CCP Note: of bronchiectasis. of these 2 causes on the management predominantly focuses *This review Cystic fibrosis Cystic Cause Table 1: Causes of bronchiectasis of 1: Causes Table Primary ciliary dyskinesia Alpha Allergic Allergic bronchopulmonary aspergillosis Autoimmune/connective Autoimmune/connective (typicallytissue diseases arthritis, SLE) rheumatoid Inflammatory bowel bowel Inflammatory diseases Congenital Congenital malformations Aspiration Humoral Humoral immunodeficiency Postinfectious* Idiopathic* and other gram-negative pathogens. lococcus aureus and other gram-negative quently, there may be also be colonization with non­ quently, there may be mycobacteria. (12%–26%), but may also also P. aeruginosa (12%–26%), but may enzae (47%–55%) and include dard culture has found evidence of a more diverse bacterial com- bacterial diverse more a of evidence found has culture dard in bronchiectasis; in one study, moremunity in the lower airways tion, perpetuating the vicious cycle of airways infection and inflam - and airways infection cycle of the vicious tion, perpetuating progression. disease presumed and destruction tissue mation, Chronic infection with certain species has been shown to correlate has been shown with certain species Chronic infection with Pseu- example, colonization clinical features. For strongly with declineof rate increased an with associated is aeruginosa domonas quality of life. and poorer health-related in lung function REVIEW mortality and is calculated using FEV capacity. hospitalizations, qualityoflife,lungfunctiondeclineandexercise useful inpredictingotherclinicaloutcomessuchasexacerbations, and four-yearmortality,buthasmorerecentlybeenfoundtobe tion. Itwasinitiallyvalidatedtopredictbothriskofhospitalization Scale score,lobesaffectedandevidenceofchronicbacterialinfec- mass index,FEV bronchiectasisseverity.com). Predictivevariablesincludeage,body patient management. scores shouldbeusedasanadjuncttoclinicalopinioninform time orrespondtointerventionhasyetbeestablished.These TheutilityofeithertheFACEDorBSIscoretochangewith (> 9). 29.2% mortalityand41.2%–80.4%hospitalizationforseverescore ity and9.9%–19.4%hospitalizationformoderatescore(5–8) 0%–9.2% hospitalizationformildscore(0–4);4.0%–11.3%mortal- E830 sis; cessationadviceshouldbeoffered. smoking isanindependentriskfactorformortalityinbronchiecta- dition isimportant.Tobaccoadirectinsulttotheairwaysand ling patientsregardinglifestylechoicesandhowtheyaffectthecon- Several modifiablefactorscanaffectprognosis;therefore,counsel- Education improve thepatient’shealth­­ exacerbation frequencyandseverity,preservelungfunction The mainaimsofmanagementaretoreducesymptoms, How shouldbronchiectasisbemanaged? Severity Index(BSI). with clinicaljudgment:theFACEDscoreandBronchiectasis disease severitymayaidmanagementdecisions. insults to the airways and preserving lung function. Assessing affected lobes)andMedicalResearchCouncilDyspneaScalescore. Pseudomonas mortality. tant, withlowerbodymassindexanindependentriskfactorfor Note: SD=standard deviation. ([mean ± SD] 2.4±1.6/yr) Recurrent chest infections Chest pain (19.0%–46.3%) Dyspnea (60.0%) Hemoptysis (26.0%–51.2%) ([mean ±SD]3834mL) Excessive sputumvolume Sputum (75.0%) Cough (90.2%–96.0%) Symptoms at presentation Box 2:Presenting signsandsymptoms of bronchiectasis The BSIcanbecalculatedusinganonlinetool(www. Two validated severity scores are currently used in conjunction Two validatedseverityscoresarecurrentlyusedinconjunction 33 32 Outcomes at four years were 0%–5.3% mortality and AnobservationalcohortstudyobservedvitaminDdefi- colonization, extent of bronchiectasis (number of 1 % predicted, Medical Research Council Dyspnea % predicted,MedicalResearchCouncilDyspnea 31,32 The FACED score predicts risk of five-year TheFACEDscorepredictsriskoffive-year 2,16 -related qualityoflife. Wheeze (21.0%–34.0%) Crackles (69.9%–73.0%) Clubbing (2.0%–3.0%) Normal examination Signs at presentation 1 34,35 % predicted, age, chronic Nutritionisalsoimpor- CMAJ | JUNE19, 2017 2,16 ; 9.9%– 31

| VOLUME 189 p 15.1 (95%confidenceinterval[CI] 8.2to22.0)versus1.8(–8.910.7), produced moresputumthanphysiotherapyalone. tonic) saline administered immediately before chest physiotherapy saline. Onestudyofeightpatientsfoundthatnebulized0.9%(iso - insufficient evidencetosupportroutineprescriptionofnebulized may reducethenumberofexacerbationsbronchiectasis. seasonal influenzaandPneumococcalvaccinationsareuptodate an exacerbationrequiresearlyreview,andensuringthatboththe change inFEV saline significantlyimprovedlung function,asmeasuredbythe in 32patientscomparing7%saline and0.9%salinefoundthat7% with isotonic(0.9%)saline.Athree-month, randomizedcrossovertrial recent studies have exploredtherole of hypertonicsalinecompared encouraged tobeactive. capacity, lessdyspneaandfewerexacerbations;patientsshouldbe proven to provide immediate benefits, with improved exercise to ensureanadequatedietaryintake. worse symptomsandchronicairwayinfection;individualsmaywish ciency tobecommoninbronchiectasis,aswellassociatedwith rehabilitation programsissummarizedinTable2. beneficial effects. Evidence that supportstheusefulness of exercise or apulmonaryrehabilitationprogramhasbeenshowntohave support, iskeytomanagement.Involvementinanexercisetraining nated bronchopulmonarysecretions,usuallywithphysiotherapy with bronchiectasis.Enhancingeffectiveexpectorationofstag- Clearance ofbronchopulmonarysecretionsisimpairedinpatients Airway clearance units], tionnaire score1.3units[–0.17to3.25units]v.0[–1.50.5 cally significantdegree(improvementinLeicesterCoughQues- improved perceived cough severity by a clinically and statisti a randomizedcrossovertrialin2009. mucus andimprovesputumtransportability. with aminimumoftwohoursdailytreatmentfor12months. 33.5 d,p=0.045)amongpatientswhohadairwayhumidification 3.63 perpatientyear,p=0.067)ofshorterduration(18.2dv. ectasis foundfewerexacerbations(2.97perpatientyear v. placebo-controlled studythatincludedpatientswithoutbronchi- tine use.Asingle,small,open-label,randomized,parallel-group, current evidenceisinsufficientforittoberecommendedrou- physiotherapy, withtechniqueandcomplianceregularlymonitored. should beassessedbyaphysiotherapistandinstructedinchest ence soastooptimizecompliance. in single techniquehasbeenfoundtobesuperior(evidenceoutlined positive expiratorypressure(PEP)andoscillatingPEPdevices.No such astheactivecycleofbreathingtechnique,posturaldrainage, (2 mL[0to6mL]v.–1[–50mL],p<0.02). to 20m)])andincreasedthevolumeofsputumexpectorated the IncrementalShuttleWalkTest[40m(15to80m)v.0(–10 <0.01. Table 3),andselectionshouldfocusonpatientabilityprefer- The efficacyofregularchestphysiotherapywasestablishedin concentration of Nebulized salineisthoughttoalterthewaterconcentrationof Although airwayhumidificationmayconfersomebenefits, There are different methods for delivering chest physiotherapy, There are different methodsfordeliveringchest physiotherapy, p 54 <0.002),increasedexercisecapacity(asmeasuredby However, a 12-month study in 40 patients comparing 6% However,a12-month studyin40patientscomparing 6% | ISSUE 24 1 % predicted from baseline at the end of the study with % predictedfrombaselineatthe end ofthestudywith 37 A deterioration in symptoms suggesting Adeteriorationinsymptomssuggesting 44–50 43 36 We suggest that all patients We suggestthatallpatients Twice-dailyphysiotherapy Exercise training has been Exercisetraininghasbeen 52 Currently, there is Currently,thereis 37,39–42 53 Other, more Other,more 38 51 -

REVIEW E831 /FVC < 70% /FVC 1 Outcome Outcome = 0.021) and a modest reduction in a modest reduction = 0.021) and No difference in sputum weight, in sputum spirometry No difference weight, in sputum dyspnea No difference spirometry score, and with ACBT sputum weight Greater drainage postural no superior to were groups treatment Both lung scores, dyspnea for physiotherapy high- and sputum production; function oscillation wall chest frequency No difference in sputum expectoration during expectoration in sputum No difference severity period; cough 24-h posttreatment all groups for improved score Significant improvement in exercise capacity in capacity in exercise improvement Significant control; v. intervention groups both 3-mo only at sustained improvements also had inspiratory that in the group follow-up muscle training and > 2 exacerbations/yr Significant improvement in exercise capacity; capacity; in exercise improvement Significant dyspnea in reported improvement significant male, FEV of efficacy: Predictors capacity; in exercise improvement Significant improvement and fatigue; dyspnea less reported and dyspnea reported capacity, in exercise fewer follow-up; at sustained not was fatigue in the subsequent 12 mo with a exacerbations exacerbation first time to longer capacity in exercise improvement Significant pulmonaryand HRQL with both rehabilitation chest v. physiotherapy and chest in no improvements alone; physiotherapy or muscle function respiratory spirometry, in either group markers inflammatory in capacity in exercise improvement Significant in HRQL improvement significant groups; both groups in both ISSUE 24 ISSUE | properties of the mucus and enhancing both mucociliary and and mucociliary both and enhancing mucus of the properties long- the in role mannitol’s rationale, this Despite clearance. cough A large, is currently unclear. of bronchiectasis term management of twice-daily double-blind trial randomized, one-year, multicentre, exacerbation in time to first found an increase inhaled mannitol (165 d v. 124 d, p with treatment Patients VOLUME 189 VOLUME | 66.5% of predicted (24.2) 66.5% of predicted 72%–76% of predicted 76% of predicted 74% of predicted 1 1 1 1 55 64%, 54% and 69% of predicted 64%, 54% and 69% of predicted 1 Intervention respectively per group respectively 63.1, 57.3, 62.9 yr age -Mean per group respectively -Mean age 64 yr age -Mean 68.6 (9.8) yr age -Mean -Mean age 63–65 yr age -Mean n = 30 sputum expectorating -Regularly due to capacity exercise -Limited bronchiectasis chest practicing -Already ≥ x 4/wk physiotherapy FEV -Mean n = 95 FEV -Mean n = 32 -FEV n = 108 71 yr age -Mean FEV -Mean n = 85 -Minimum of 2 exacerbations/yr Dyspnea Council Research -Medical ≥ 1 score Scale FEV -Mean JUNE 19, 2017 | 44–46 (by a mean of 90 mL90 of mean a (by 1 = forced expiratory volume in the first second, FVC = forced vital capacity, HRQL = health-related quality of life. HRQL = health-related capacity, vital = forced FVC second, in the first volume expiratory = forced 1 CMAJ 1 session ACBT with head-down tilt v. 1 session without tilt v. with head-down 1 session ACBT 4 wk of Flutter* v. 4 wk of ACBT all drainage, and postural ACBT v. ACBT v. Flutter* 1 wk assessed over 15 d of 5 d/wk for sessions administered Twice-daily v. techniques) (various physiotherapy chest traditional (using the Vest oscillation wall chest high-frequency no physiotherapy v. System) Airway Clearance 3 nonconsecutive sessions over 7 d of autogenic drainage drainage 7 d of autogenic over sessions 3 nonconsecutive position v. open in lateral with glottis expiration slow v. pressure expiratory positive temporary Intervention Patients 19 17 30 30 31 8-wk pulmonary rehabilitation 8-wk pulmonary rehabilitation 8-wk pulmonary v. program and program rehabilitation v. muscle training inspiratory control 8-wk pulmonary and program rehabilitation chest twice-daily twice-daily v. physiotherapy physiotherapy chest 6- or 8-wk pulmonary v. program rehabilitation in same with COPD patients program 3-wk pulmonary program rehabilitation and training 8 wks of exercise of airwayreview clearance control v. technique 44 42

46 47 45 48 41 40 37 39 Inhalation of the naturally occurring sugar mannitol is thought sugar mannitol of the naturally occurring Inhalation Crossover study (1999) study Crossover Retrospective analysis Retrospective (2015) Note: ACBT = active cycle of breathing technique. of breathing cycle = active ACBT Note: device. pressure expiratory is an oscillating positive *The Flutter Study design (year) Study Table 3: Studies comparing physiotherapy techniques in stable bronchiectasis in stable techniques physiotherapy comparing 3: Studies Table Note: COPD = chronic obstructive pulmonary FEV disease, obstructive = chronic COPD Note: Table 2: Evidence for exercise and pulmonary rehabilitation exercise for 2: Evidence Table design (year) Study Randomized Randomized single-blind trial (2014) Randomized Randomized study pilot controlled (2012) study Retrospective (2011) Randomized trial (2005) controlled Randomized crossover crossover Randomized (2002) study prospective Randomized (2007) study crossover Randomized (2016) study Randomized trial Randomized (2013) to alter the osmotic gradient in the airway lumen, changing the the airway lumen, osmotic gradient in to alter the saline and 0.9% saline found no clinical superiority of hypertonic superiority no clinical saline found and 0.9% saline an improve- groups experiencing isotonic saline, with both saline over FEV in and life of quality health-related in ment [11 to 169 mL] at 6 mo only. This effect was not sustained at 12 mo). was not sustained at 6 mo only. This effect [11 to 169 mL] REVIEW E832 other mucolyticsinthemanagementofbronchiectasis. ommended foruse. in bronchiectasisandneitheroralnorinhaledNACarecurrentlyrec- respiratory secretions.InhaledNAChasnotbeensufficientlystudied through its antioxidant properties owing to its low bioavailability in impact onlungfunctionorsputumbacteriologicalproperties. CI 1.48to1.94]withmannitolv.1.84[1.612.10],p reduction inexacerbationrate(annual1.69[95% the numberofdaysantibioticuse,buttherewasnosignificant significant reductioninFEV antibiotics andagreaterrateofhospitaladmissions,aswell ment, patientshadahigherrateofexacerbations,increaseduse 24 weeksin349patientswithbronchiectasisfoundthattreat- ized, double-blindcontrolledtrialoftreatmentwithrhDNAasefor ration, airwayclearanceandlungfunction.However,arandom- cleave theDNA,reducingsputumviscosityandimprovingexpecto- lation of recombinant human deoxyribonuclease (rhDNAse) should inflamed andinfectedairways.Ithasbeenhypothesizedthatinha- persistent anduncontrolledneutrophilicactivityinthechronically ties oftheviscouspolymerdeoxyribonucleicacid(DNA)releasedby although notspecificallybronchiectasis. trolled trialsfoundsomeevidencefororalNACinchronicbronchitis, ied forbronchiectasis.Ameta-analysisofeightrandomizedcon- harmful andshouldbeavoidedbypatientswithbronchiectasis. (2012) study EMBRACE (2013) study BLESS Note: AE=adverse FEV event, (year) Study Table 4:Evidence from recent randomized controlled trialsof macrolides (2013) BAT study There islittleevidence,andcertainlynorecentfor Purulent, tenaciousairwaysecretionscontainexcessivequanti- Oral andinhaledN-acetylcysteine(NAC)havenotbeenwellstud- 67 66 65 placebo times perwkv. azithromycin 3 500 mg placebo v.erythromycin daily 400 mgtwice placebo azithromycin v. 250 mgdaily Treatment 1 =forced expiratory volume inthefirst second, HRQL=health-related quality oflife. 1 . 57 Inhalation of rhDNAse appears to be InhalationofrhDNAseappearstobe 6-mo follow-up 6-mo treatment 4-wk washout 48-wk treatment 90-d run-out 12-mo treatment Study duration 58 Oral NAC is thought to act OralNACisthoughttoact CMAJ | JUNE19, 2017 = 0.31) and no =0.31)andno patients Number 141 117 83 of of 56 | VOLUME 189 preceding yr with pathogens in ≥ 1 sputumculture ≥ x 3exacerbations/yr ≥ x 1exacerbation/yr ≥ x 2exacerbations/yr adverse effects,suchasadrenalsuppression. siveness andexcessivesputumproduction,balancedwiththeriskof factors suchaspresenceofairflowobstruction,airwayhyperrespon- these agentsamongpatientswithoutcomorbiditiesmustconsider patients takingregularinhaledcorticosteroids. patients withbronchiectasishavefoundfewerinflammatorycellsin morbidities suchasasthmaorchronicobstructivepulmonarydisease. corticosteroids andβ There is insufficientevidencetosupportroutineprescriptionofinhaled Inhaled corticosteroidsandβ-agonists improvement of–5.3unitsintotalscore,p George’s RespiratoryQuestionnaire,withaclinicalandstatistical provided symptomaticimprovement(asmeasuredbytheSt. ever, thecombinedinhaledcorticosteroid/long-actingβ bination versusahigh-dosecorticosteroidusedinisolation.How- medium-strength inhaledcorticosteroid/long-actingβ patients with bronchiectasis and airflow obstruction who received a study found no impact on lung function or sputum bacteriology in bacteriology. seen intermsoflungfunction,exacerbationfrequencyorsputum placebo-controlled trial a reductioninsputumvolume,bothrandomized,double-blind, and health-relatedqualityoflifehavebeendemonstrated,aswell ment withinhaledsteroids.Improvementsinreportedsymptoms are veryfewstudiesexploringtheclinicalbenefitofroutinetreat- controlled crossover trial, characteristics Previous small studies of sputum and bronchial epithelium in Previous smallstudiesofsputumandbronchialepitheliumin Patient | ISSUE 24 The most recent randomized, double-blind parallel The mostrecentrandomized,double-blindparallel -agonists in bronchiectasis without coexisting -agonists inbronchiectasiswithoutcoexisting -Improvement inFEV -Fewer exacerbations (0[0–1]v. 2[1–3]) With azithromycin v. placebo: -No macrolide resistance testing performed -Well tolerated, with59reported AEsv. 65 (190–331) dv. 85(52–113)d -Annually, longer timeto first exacerbation 239 during treatment and42%annually -62% relative reduction inexacerbation rate With azithromycin v. placebo: -Less declineinpostbronchodilator FEV (–5.4 gv. –1.7greduction) -Significant reduction in24-hsputumweight -Fewer exacerbations (76v. 114) v.With erythromycin placebo: -Well tolerated; 28.8%v. 25.9%reporting AEs -Increased macrolide resistance: 27.7%v. 0.04% predicted (–1.6%v. –4.0%) patients v. 26%in22patients patients at baseline increased to 88%in20 -Increased macrolide resistance: 35%in8 diarrhea -Well tolerated, despite increased relative riskof -Improved HRQL 61 andarandomized,double-blind,placebo- 62 but little or no clinical impact has been but little or no clinical impact has been Significant results andoutcomes 1 % predicted (+1.03% v. –0.1%) 64 =0.006). 59,60 However, there However,there -agonist com- 63 The use of Theuseof 1 % -agonist -agonist REVIEW - E833 biotics in bronchi- Main findings — although more evi more although — P. aeruginosa This evidence is summarized in Table 5. Reduced sputum bacterial density; fewer density; fewer sputum bacterial Reduced tolerated well exacerbations; density; sputum bacterial Reduced 35% sputum purulence; improved eradication pathogen density; 30.8% sputum bacterial Reduced and 92.8% Pseudomonas eradication reduced pathogens; in other eradication exercise improved airways inflammation; HRQL; fewer improved capacity; first time to increased exacerbations; not effects treatment exacerbation; during follow-up sustained Reduced sputum bacterial density; density; sputum bacterial Reduced exacerbation; first time to increased HRQL improved No improvement in respiratory symptoms; symptoms; in respiratory No improvement prolonged; not exacerbation first time to events; adverse treatment-related more than with treatment discontinuations more placebo 68–72 ISSUE 24 ISSUE | Patients Overall, these studies provide support for the role of long-termOverall, these studies provide support for Long-term antibiotic treatment offers a reasonable therapeuticLong-term antibiotic - bron of nature heterogeneous the given particularly needed, is dence trials the criteria in inclusion patient strict the chiectasis and antibiotics in patients with bronchiectasis and chronic infection —antibiotics in patients with bronchiectasis with infected those particularly nontuberculous mycobacteria infection, abnormal liver function liver abnormal infection, mycobacteria nontuberculous pos- Counselling regarding abnormality. and electrocardiogram are needed studies Further prudent. be loss would hearing sible - ensure maxi to and regimen macrolide optimum the to establish resistance Macrolide effects. adverse minimal with benefit mum study. needs further who use it for bronchiectasis among those is that reducing the bacterial burden and option; the rationale - may promote healing of the bron improving airway inflammation exacerbations, to fewer and leading symptoms limiting tree, chial better health-related quality of life. Despiteimproved mortality and studies of long-term anti­ this, there have been few or oral antibiotic agents are currently licensedectasis and no inhaled in North America. In an attemptfor long-term use in bronchiectasis need for evidence-guided treatment, the lastto address this urgent ofrole the exploring trials new important several seen have years six all for this indication. These studies have long-term antibiotics with delivery drug targeted offering antibiotics, inhaled on focused bronchospasm of risk a with but effects, adverse systemic minimal and increased expense. n = 42 Chronic Criterion: with sputum colonization aeruginosa P. n = 124 Chronic Criterion: with sputum colonization any pathogen n = 60 Chronic Criterion: with sputum colonization any pathogen Study 1: n = 266 Study 2: n = 274 Study Chronic Criterion: with sputum colonization pathogens gram-negative exclusively (but not ) Haemophilus influenzae n = 144 chronic Criterion: with sputum colonization Pseudomonas aeruginosa VOLUME 189 VOLUME |

65 while self- 67 JUNE 19, 2017 | Dose and duration Dose Dual-release liposomal Dual-release 150/60 mg ciprofloxacin 28 days on, 28 days off 24 weeks for placebo v. Dry inhaled powder 32.5 mg ciprofloxacin 28 days daily for twice twice 80 mg nebulized 12 for placebo daily v. months with 3-month follow-up 1 million IU twice daily 1 million IU twice 6 months for placebo v. 75 mg daily off on, 4 weeks 4 weeks placebo v. 16 weeks for with 4-week Followed open label This may be particularly CMAJ

65–67 65,66 Study design Study Randomized, Randomized, single-blind controlled trial Multicentre, Multicentre, double- randomized, blind, placebo- trial controlled Multicentre, double- randomized, blind, placebo- trial controlled Multicentre, Multicentre, double- randomized, blind, placebo- trial controlled Two multicentre, multicentre, Two double-blind, placebo- randomized trials controlled 71 70 72 68 69 Although the macrolides were generally well tolerated by patientsAlthough the macrolides Given macrolides’ potential adverse effects, patients should should effects, patients potential adverse Given macrolides’ Quinolone: ciprofloxacin Aminoglycoside: gentamicin Quinolone: ciprofloxacin Polymyxin: Polymyxin: colistin Note: HRQL = health-related quality of life, IU = international units. IU = international quality of life, HRQL = health-related Note: Antibiotic class Antibiotic and agent Table 5: Summary of recent evidence for long-term inhaled antibiotic therapy inhaled antibiotic long-term for evidence 5: Summary recent of Table Monobactam: Monobactam: aztreonam in these studies, resistance did develop with treatment in the twoin these studies, resistance as an outcome. studies that explored this

Although the antibacterial properties of macrolides were discov- of macrolides antibacterial properties Although the important been shown to have these agents have also ered first, proper- these immunomodulatory effects. It is immunomodulatory - impair chemotaxis, cell inflammatory of inhibition as such — ties and by activated neutrophils generation ment of superoxide be to them caused that — hypersecretion mucus of impairment - agents in bronchiectasis. Three random considered as long-term provide evidence to support a trial of long- ized controlled trials in patients with frequent exacerbations.term macrolide therapy in Table 4. Their findings are summarized Long-term macrolide and antibiotic therapy antibiotic and macrolide Long-term be screened before commencing treatment for any evidence of of evidence any for treatment commencing before screened be relevant for patients infected with nontuberculous mycobacteriarelevant for patients the an important therapeutic role, should where macrolides have - according to current international guide patients require treatment Cardiovascular events,lines for treatment of mycobacterial infection. reported with macro- hepatotoxicity and dysacusis have also been no hepatotoxic- lide treatment. The aforementioned trials reported angina), ity, and a single cardiovascular event (unstable reported auditory problems — occurring in 12% in the treatment armreported auditory problems — occurring in 12% in one study. and 10% in the placebo arm — were reported REVIEW review of 34 patients who received transplants (33 double-lung and review of34patientswhoreceivedtransplants(33double-lungand bronchiectasis andtheirmanagementshouldbeoptimized. asthma andchronicobstructivepulmonarydisease—complicate comorbidities —suchasgastroesophagealreflux,postnasaldrip, found 68.5%weresymptomfreeat4.5yearsfromsurgery. gest thatanFEV ered forreferraltransplant.Currenttransplantguidelinessug- compliance withmaximalmedicalmanagementshouldbeconsid- E834 stantial clinicalimprovement; surgery finding84%asymptomaticand10.7%describingsub- a studyof75patientswithmedian15.3-monthfollow-upfrom outcomes fromretrospectivesurgicalcasereviewsaregood,with bidity, suchasrecurrentorlife-threateninghemoptysis.Reported refractory tomedicalmanagementandcausingsubstantialmor- Surgery isreservedpredominantlyforlocalizeddiseasethat Surgery andtransplant anxiety in 39.8% to 55% of patients. tasis, withstudiesfindingevidenceofdepressionin21.1%to34%and Anxiety anddepressionarefrequentamongpatientswithbronchiec- Management ofcomorbidities drug FEV account tolerability(withachallengedosemeasuringpre-andpost- published todate.Considerationofantibioticchoiceshouldtakeinto year mortalityrisk)oranFEV factors andtheirappropriatemanagementisimportant. bronchiectasis; reviewofothermodifiablecardiovasculardiseaserisk suggested anincreasedriskofcardiovasculardiseaseinpatientswith agement ofclinicallydistressingmentalillness.Recentevidencehas mental stateiswarranted,alongwithappropriatereferralforman- efficacy, toxicityandsputumculturesregardingongoingneed. be reviewedregularly(everysixmonths)withassessmentofclinical We suggestthatthosecommencedonlong-termantibioticsshould rhinosinusitis) addressed before long-term antibiotics are considered. ment optimized and other associated comorbidities (such as reflux or mycobacterial status should be reviewed, airway clearance manage- Antimicrobial stewardshipisimportantandthepatient’sculture tors forareferraltothetransplantclinic. sive hemoptysis,restinghypoxemiaandhypercapniaareallindica - decline, frequenthospitaladmissions,worseningcachexiaormas- • • • • • • Box 3:UnansweredQuestions Patients with bronchiectasis and advanced lung disease despite Patients withbronchiectasisandadvancedlungdiseasedespite neutrophilic airwayshavearoleinbronchiectasis? Will newtherapeuticagentstargeting inflammationof and inwhom? Do long-termoralantibioticsoffer a goodtherapeuticoption, bronchiectatic airways? What istheroleofmacrolidetherapy ininducingresistance and howcanthesebemodified? What factorscanidentifypatientsatriskofdiseaseprogression than standardculture?Whatwouldtheirclinicalapplicationbe? Is therearoleforbacteriologicaldiagnostictechniquesother What arethemaincausesofbronchiectasisinCanada? 1 mandatory for all patients), colonizing pathogen and cost. mandatoryforallpatients),colonizingpathogenandcost. 1

≤ 30%predicted(giventheassociatedhighone- 77 1 >30%predictedbutwithrapid a separate study of 277 patients aseparatestudyof277patients 73,74 Frequent review of patients’ Frequentreviewofpatients’ 79 CMAJ A recent retrospective Arecentretrospective | JUNE19, 2017 75,76 78

Other Other | VOLUME 189 10. 11. 12.

25.

one-year survivalof85%andfive-year73%. 1 single-lung) for bronchiectasis between 1992 and 2014 found a 24. 23. 13. References ectasis aswelltreatmentofthedisease. tinue toadvanceourknowledgeandunderstandingofbronchi- consistently well-designed studies are needed in order to con questions remainunanswered(seeBox3)andfurther,larger, the managementofadultswithbronchiectasis.However,many Accumulating andincreasinglyrobustevidencenowsupports Conclusion

21. 14. 15.

22. 19. 20. 17. 16. 18. 3 8 2 4 9 7 1. 6. 5...... Laennec 2015; Reid 4th ed.London(UK):Longman;1834. chiectasis inadultsanditscorrelationtodiseaseseverity. King Lonni 2015; bronchiectasis inaChineseHanpopulation:prospectivestudy. King cohort study.EurRespirJ2016;47:186-93. mortality ofbronchiectasis intheUKfrom2004 to 2013: apopulation-based Wilson pulmonary functioninpatientswithbronchiectasis. EurRespirJ2006;28:974-9. senting clinicalfeaturesofadultbronchiectasis. 2013; fibrosis bronchiectasis:aprospectiveobservationalcohortstudy. Anwar J RespirCritCareMed2013;188:647-56. Qi quality oflifepatients withbronchiectasis.EurRespirJ1997 ; Martínez-García Davies bronchiectasis. AmJRespirCritCareMed 2012;186:657-65. treatment reducesairwayandsystemic inflammationinnon-cysticfibrosis Chalmers 2001;164:1628-32. Martínez-García findings atbronchoalveolarlavage.AJRAmJRoentgenol1997;168:1535-40. infection: CTassessmentandcorrelationwithpulmonaryfunctiontests Quint determinants inpatientswithclinicallystablebronchiectasis. Pasteur 128: patients withclinicallystablebronchiectasis. tors inpatientswithbronchiectasis. McShane ectasis. RespirMed2007;101:1163-70. King chiectasis: microbiologicalpatternandriskfactors.Thorax2002;57:15-9. Gupta with bronchiectasisinpatientsCOPD.Chest2011;140:1130-7. Mandal scans insevereasthma.Chest2009;136:1521-8. Shoemark Angrill adult bronchiectasis.RespirMed2007;101:1633-8. with thin-sectionCTandhelicalCT. Lucidarme put AssistTomogr1996;20:15-9. ment ofbronchiectasis:comparisonHRCTandspiralvolumetricCT. characterization ofbronchiectasisinanagingcohort. exacerbations andqualityoflifeinbronchiectasis. Angrill Dodd Nicotra van derBruggen-Bogaarts fibrosis bronchiectasis.SeminRespirCritCareMed2015;36:194-206. Q 739- , LM. PT, 20: 12: 107: MA, PT, Wang JD, S JK, S, GA, J, J, G, CB, , MB, 917- 45. MC, P 1764- Reduction inbronchialsubdivisionbronchiectasis. Holdsworth Chalmers R. Agustí Agustí Siddiqui 1001- Holdsworth , PJ, Neal Wells Millett Lavelle | JD, McDonnell Morice A, ISSUE 24 O Jones A treatiseonthediseasesofchestandmediateauscultation. Rivera W 24. Helliwell , Naureckas Ozerovitch 70. Grenier , Smith 7 Li DE, AU, C, C, . MA, MÁ, ER, T LP, PW, M S, de Celis AH, De Celis , JD, St John Doffman et al. , Perpiñá-Tordera SR, Soler-Cataluña Haldar Joshi SM, Dale P MP, MJ, Fabre SR, Goeminne Chalmers O’Leary , Coche ET, Freezer L, Houghton Aetiology and clinical characteristics of patients with Aetiology andclinicalcharacteristicsofpatientswith AM, Worthy McHugh Freezer R, BA, R, M, Wilson Tino R P, A S, et al. , et al. , et al. et al. van derBruggen E et al. et al. et al. CJ, et al. , NJ, G, et al. JD, PC, SA, Bacterial colonisationinpatientswithbron- NJ, R. Bronchial inflammationandcolonizationin et al. Am JRespirCritCareMed Radiology BJ, et al. Clinical, pathophysiologic, and microbiologic Clinical, pathophysiologic,andmicrobiologic SJ, et al. Changes in the incidence, prevalence and JJ, Qualitative analysis of high-resolution CT Bronchial dilatationinpatientswithHIV The effectofPseudomonasaeruginosaon et al. Imaging incysticfibrosisandnon-cystic M et al. Aetiology inadultpatientswithbronchi- et al. Bronchiectasis: comparative assessment Bronchiectasis: comparativeassessment et al. , et al. et al. Donat Sanz Román-Sánchez Non-cystic fibrosis bronchiectasis. Effect ofsputumbacteriologyonthe Characterisation of theonsetand pre- Symptoms ofairwayrefluxpredict Etiology ofnon-cysticfibrosisbron- Phenotyping adults with non-cystic Phenotyping adultswithnon-cystic An investigationintocausativefac- Microbiologic follow-upstudyin 1996; Short- andlong-termantibiotic Respir Med HM, Respir Med Chest Am JRespir CritCare Med 200: Y, van Waes et al. 673- 1995; P Thorax 2006; , 9 Ann Am Thorac Soc et al. Factors associated 2000; 2013; . 108: 80 PF, 10:1754-60. 100: 1950; 955- Quality-of-life Quality-of-life 162: 107: et al. Chest Respirology 2183- Respir Med 61. 1277- 5 1008- : 233- Assess- J Com- 9 2005 . 84. 13. 47. Am - ;​

REVIEW

. 7 2011;​ Chest Chest 2016; E835 723- 158: Eur Respir J Inhaled, dual dual Inhaled, Am J Respir Crit Clinical efficacy Presence of anx- 1998; Lancet Respir Med 21. et al. et al. , P C, 209- 22: Factors related to depression Lung transplantation for non- for transplantation Lung Am J Respir Crit Care Med Surgical management of bron- Inhaled colistin in patients with Neuropsychiatr Dis Treat 2000; Cisneros et al. - Adrenal suppression in bronchiec , et al. et Effect of azithromycin maintenance Effect of azithromycin maintenance Effect of long-term, low-dose eryth- G,

Efficacy of oral long-term N-acetylcys- Efficacy of oral G et al. . investigators. ORBIT-2 Aztreonam for inhalation solution in Aztreonam for inhalation solution in Bronchiectasis and the risk of cardio- of risk the and Bronchiectasis et al. Treatment of idiopathic bronchiectasis of idiopathic Treatment H, Catalán-Serra lu Increases in CD4+ T lymphocytes, mac- Increases in CD4+ P, et al. A randomized controlled trial of nebulized SH, et al. et al. Azithromycin for prevention of exacerba- Surgical management of bronchiectasis: Surgical management of bronchiectasis: Clin Ther et al. Ciprofloxacin dry powder for inhalation in Am J Respir Crit Care Med JJ, , et al. et et al. Y, A consensus document for the selection of et al. Inhaled steroids in patients with bronchiecta- patients with Inhaled steroids in ; al.; et R RA, , et al. , , MA, et al. Bronchiectasis severity is an independent risk P Suhling Inhaled fluticasone reduces sputum inflamma- Inhaled fluticasone reduces A JR, JS, et al. Günlüoğ et al. et al. Inhaled fluticasone in bronchiectasis: a 12-monthInhaled fluticasone in bronchiectasis: M, , , , et al. et et al. CJ, G FC, N, , E A Wilkinson F et al. . et al. Hurst Stienstra Flume 4 PA, et al. Stockley 43. Ruffmann Ilowite JE, , TM, McGuckin WK, Özkan Allen ER, CS, P PL, De Soyza De Ucvet AE, 121- Doherty , Fattahi Masoum Humbert JW, 239- AF, Soler-Cataluña , , Karalus B D Corris EY, 86: ML, Ho Polverino Fernandes Vasconcelos L, 60: AA, JR, Lam SZ, , AM, Quinn C, MÁ, T Ringshausen Millett KC, . Berthet P, RM, 34. PL, Barker 1992; 8 15. J, Foweraker 2005; V, de Graaff Bilton Martin Govan O’Donnell ISSUE 24 ISSUE Haghi Ho Tan EM, Ozturk J, Johnston | AE, Welte Tomlinson 461- Bedi CS, . , 1329- Jayaram Bentley , , DJ, R, 10. Benden 1107- DJ, 9 S

AF, J, R MP, JS, KW, IE, KW, C, Thorax M, D, 141: 41: 113: 491- Respir Med 3005- treatment on infectious exacerbations among patients with non-cystic fibrosis non-cystic with patients among exacerbations infectious on treatment controlled trial. JAMA 2013;309:1251-9. bronchiectasis: the BAT randomized Serisier tasis and the impact of inhaled corticosteroids. Eur Respir J 2008;32:1047-52. tasis and the impact of inhaled Altenburg release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): release liposomal ciprofloxacin in non-cystic fibrosis Thorax 2013;68:812-7. a randomised, double-blind, placebo-controlled trial. Wilson bronchiectasis and chronic Pseudomonas aeruginosa infection. Care Med 2014;189:975-82. Serisier sis. Martínez-García and safety of budesonide-formoterol in non-cystic fibrosis bronchiectasis. and safety of budesonide-formoterol 2012; Holme non-cystic fibrosis bronchiectasis: a phase II randomised study. non-cystic fibrosis bronchiectasis: a phase II randomised 2013; Murray DNase I. rhDNase Study Group. recombinant human with aerosolized O’Donnell J Heart Lung Transplant 2015;34:1-15. Rademacher and anxiety in adults with bronchiectasis. gentamicin in non-cystic fibrosis bronchiectasis. romycin on pulmonary exacerbations among patients with non-cystic fibrosis romycin on pulmonary exacerbations among patients JAMA 2013;309:1260-7. bronchiectasis: the BLESS randomized controlled trial. Wong and AIR-BX2): two patients with non-cystic fibrosis bronchiectasis (AIR-BX1 trials. randomised double-blind, placebo-controlled phase 3 2014;2:738-49. Haworth 183: Girón Moreno 1998; Grandjean Gaga Tsang rophages, neutrophils and interleukin 8 positive cells in the airways of patients positive cells in the airways and interleukin 8 rophages, neutrophils 1998;53:685-91. with bronchiectasis. Thorax Tsang 12: iety and depression in patients with bronchiectasis unrelated to cystic fibrosis. iety and depression in patients with bronchiectasis unrelated Arch Bronconeumol 2013;49:415-20. Özgün Niksarlioglu Navaratnam teine in chronic bronchopulmonary disease: a meta-analysis of published double- a meta-analysis of published bronchopulmonary disease: teine in chronic clinical trials. blind, placebo-controlled tory indices in severe bronchiectasis. study. Elborn cystic fibrosis bronchiectasis. Respir Med 2016;115:60-5. tions in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double- randomised, a (EMBRACE): bronchiectasis fibrosis non-cystic in tions . blind, placebo-controlled trial. Lancet 2012;380:660-7 Barker vascular disease: a population-based study. Thorax 2017;72:161-6. Evans the indications and outcomes. Surg Today 2010;40:26-30. Bagheri factor for vascular disease in a Bronchiectasis Cohort. Chest 2017;151:383-8. Gursoy lung transplant candidates: 2014 — an update from the Pulmonary Transplan- tation Council of the International Society for Heart and Lung Transplantation. chiectasis: analysis of 277 patients. Thorac Cardiovasc Surg 2010;58:291-4. Weill Competing interests: None declared. Affiliation: Department of Medicine, Division of Pulmonary Medicine, University of Alberta, Edmonton, Alta. This article has been peer reviewed. Correspondence to: Maeve Smith, [email protected] 66. 65. 71. 70. 63. 64. 72. 57. 80. 67. 69. 73. 58. 59. 61. 60. 74. 75. 62. 68. 76. 78. 77. 79. VOLUME 189 VOLUME |

- . . 7 41. 9 67. 10. 21. Tho- . 85. 18. 5 Respir 661- 536- 21. 816- 1073- 1357- 576- 1204- 181- 1110- : 106: 13: 69: 156: 43: 8 28: 104: 189: 71: Chron Respir Chron Respir 2013; 2012; 2014; 2014; 2003; 1997; 2006; 2010; 2014; 2016; JUNE 19, 2017 | Thorax Thorax Multidimensional approach Respir Med - mycobac Non-tuberculous Eur Respir J Respirology Respir Med Eur Respir J BMC Pulm Med CMAJ Clinical measures of disease inClinical measures of disease et al. , et al. et M Vitamin-D deficiency is associated Vitamin-D deficiency is associated The effects of oscillating positive The effects of oscillating positive The active cycle of breathing tech- et al. Randomised crossover study of the Multidimensional severity assessment 64. G, Mortality in non-cystic fibrosis bron- Mortality in non-cystic fibrosis , L The long term effect of inhaled hyper- Validation of the St. George’s Respira- Validation of Short-term effects of three slow expira- Use of nebulised saline and nebulised and saline nebulised of Use Nontuberculous mycobacteria in bron- Nontuberculous The bronchiectasis severity index. An inter- The bronchiectasis severity index. Predictors of mortality in hospitalized hospitalized Predictors of mortality in et al. 357- Effects of pulmonary rehabilitation in Effects of pulmonary rehabilitation in Additive effect of pneumococcal vaccine et al. Am J Respir Crit Care Med et al. et al. et al. et al. Airway clearance in bronchiectasis: a ran- Am J Respir Crit Care Med Am J Respir Crit , A pilot study of pulmonary rehabilitation A pilot study of pulmonary rehabilitation C, . , The clinical utility of long-term humidifica- Davies S Effectiveness of treatment with high-frequency et al. 8 et al. J, et al. J D, et al. et 102: et al. et al. PC, , JS. , A randomised crossover trial of chest physio- et al. Bronchiectasis in secondary care: a compre a care: secondary in Bronchiectasis D et al. S LJ, A randomized evaluation of the acute efficacy, et al. N, , . . Vendrell Relat CJ, 446- BM, et al. NJ, The short and long term effects of exercise train- S Exercise training and inspiratory muscle training muscle inspiratory and training Exercise , et al. B-305 Study Investigators. Inhaled mannitol for non- et al. , Effects of pulmonary rehabilitation in bronchiec- Effects of pulmonary rehabilitation M, AT. , , 2016; JS J D

L Cuthbertson 57: L, N Ashley Martí SL. Effect of osmolality on mucociliary transportability and Docherty Ruttens Elborn , et al. , Innes Hill Borg et al. Aliberti Lorensini et al. S J Pengelley CJ, et al. I, , Goeminne Chen PJ. P , Hill BJ, TS, 2002; O’Leary JM, N, Kope Nebulised 7% hypertonic saline improves lung function AF, JL, S Elborn Y, Thomas RG, HG, . Screaton HC, CJ, SC, Adamo Ozerovitch , , , 7 , de Gracia RA, , S Landucci Vilaró Zeng Cole Jayaram J G

PW, , MK, , NM. M, M F Hill

B S, P, 731- MÁ, Harrison Thorax Barker PJ, Cecins Physiotherapy Nawrot , Aliberti McHugh Bradley Stirling Ohkusa G AL, Goeminne 68: Khan Pentland Jenkins CS, CJ, Gemmell Jones van der Gast French Sidhu PC, A, MJ, JE, Murphy Aiello Wills JD, Stockley Robert Cardini , 15:44. JD, CH, , Young , , , Lee , Tino Williamson JD, P Y MP, Hill A PP, A C, , SJ, GB, F, CB, NM, 2013; McAuley T, D MG

HK, AL, H, AL, Res 2014;​ Furumoto ing in non-cystic fibrosis bronchiectasis — a randomised controlled trial. ing in non-cystic fibrosis bronchiectasis — a randomised -30. tasis: a retrospective study. Chron Respir Dis 2011;8:21 Newall . niques — to tip or not to tip? Respir Med 1999;93:660-5 Thompson Eaton 2009;34:1086-92. therapy in non-cystic fibrosis bronchiectasis. Eur Respir J Cecins in non-cystic fibrosisFlutter device and the active cycle of breathing technique bronchiectasis. patients with non-cystic fibrosis bronchiectasis: a retrospective analysis of of analysis retrospective a bronchiectasis: fibrosis non-cystic with patients 2015;89:525-33. clinical and functional predictors of efficacy. Respiration Mandal and influenza vaccine on acute exacerbation in patients with chronic lung dis- and influenza vaccine on acute exacerbation in patients ease. Vaccine 2008;26:4284-9. Zanini rax 2013;68:39-47. Lee with chronic bacterial colonisation and disease severity in bronchiectasis. severity disease and colonisation with chronic bacterial acceptability and tolerability of flutter and active cycle of breathing with and acceptability and tolerability of flutter and active cycle without postural drainage in non-cystic fibrosis bronchiectasis. Dis 2007;4:23-30. Herrero-Cortina and chest physiotherapy versus chest physiotherapy alone in bronchiectasis. in alone physiotherapy chest versus physiotherapy chest and Respir Med 2012;106:1647-54. Ong chiectasis: a prospective cohort analysis. Respir Med 2014;108:287-96. chiectasis: a prospective cohort Chalmers Wickremasinghe Sutton in patients with bronchiectasis. Thorax 2005;60:943-8. Murray tory airway clearance techniques in patients with bronchiectasis: a randomised crossover trial. Nicolini Lee Goeminne Chalmers Martínez-García Kelly correlate with airway microbiota composition. adult non-CF bronchiectasis Thorax tory Questionnaire in bronchiectasis. tory Questionnaire cystic fibrosis bronchiectasis: a randomised, controlled trial. chest wall oscillation in patients with bronchiectasis. Finklea patients with acute exacerbation of bronchiectasis. patients with acute exacerbation McDonnell Rogers to non-cystic fibrosis bronchiectasis: the FACED score. to non-cystic fibrosis bronchiectasis: 2005;60:1045-51. with bronchiectasis. Thorax teria in patients Fowler and quality of life in bronchiectasis. Respir Med 2011;105:1831-5. Nicolson domized crossover trial of active cycle of breathing techniques (incorporating postural drainage and vibration) versus test of incremental respiratory endur- ance. Chron Respir Dis 2004;1:127-30. Rea expiratory pressure therapy in adults with stable non-cystic fibrosis bronchiec- tasis: a systematic review. Chron Respir Dis 2015;12:36-46. Patterson tion therapy in chronic airway disease. Respir Med 2010;104:525-33. Shibuya national derivation and validation study. national derivation and validation in bronchiectasis: an analysis of seven European cohorts. in bronchiectasis: an analysis and patient characteristics. chiectasis: prevalence -92. 2003;14:488 of a neglected disease. Eur J Intern Med hensive profile Wilson Bilton terbutaline as an adjunct to chest physiotherapy. Thorax 1988;43:57-60. Kellett tonic saline 6% in non-cystic fibrosis bronchiectasis. rheology of cystic fibrosis and bronchiectasis sputum. 38. 42. 45. 46. 44. 40. 39. 37. 47. 41. 36. 28. 53. 43. 48. 49.

35. 32. 31. 26. 34. 33. 30. 29. 55. 51. 50. 52. 27. 56. 54.