Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. taeist nac ptmcerneaeamjrteaetcami Fadtetetwt ons alfa dornase with treatment and CF in benefit aim of therapeutic be major to accepted a widely are been clearance has sputum enhance to Strategies disease. mortality the of of 80% a manifestations than by downstream more and for target inflammation accounts CF lifetime and which with patient’s infection, failure, patients respiratory obstruction, the chronic of over in of occurrence function cycle the lung The to contributes in tissues. ultimately decline pulmonary infections progressive the these in a to inflammation extra- by chronic response of characterized in concentrations is accumulate high fibrosis that very Cystic leukocytes contain degenerating fibrosis by parenchyma cystic released with lung DNA individuals of cellular of loss secretions pulmonary with glandular Purulent the fibrosis chronic of and progressive infections obstruction al- bacterial response, with airways, recurrent secretions inflammatory patients, the function thick CF persistent In of pediatric induce production In clearance. the colonisations damage. mucus to epithelial normal progressive lead prevent and transport may ducts ionic epithelia which the respiratory liquid of across surface alter- terations airways’ electrolytes reabsorption the the water the patients, of increased of defects CF in dehydration cause In results (CFTR) then (CF). regulator which fibrosis conductance transmembrane cystic transport, fibrosis in cystic disease the of lung ation characterizes improve clearance to mucociliary CF Impaired practice. routine clinical management. in in CF alfa patients on dornase Introduction 27 guidelines CF of international of for 1. use with panel alfa agreement appropriate in dornase most a patients, the of very on in or define use outcomes Full based to long-term therapeutic Results: used and method, to CF. was function consensus with Delphi related lung method A patients online issues from of Delphi Method: several care an Modified specialists medical on by among patients. in Conclusions: reached experts CF consensus appraised was six for of was of consensus (rhDNase) level Committee agents high Scientific alfa the mucoactive a dornase investigate by CF of to coordinated in use pulmonologists, aimed therapeutic prescribing We progressive of a appropriate reduce appropriateness lifetime. to on and on patient’s clearance Centers the sputum CF enhance over to Italian function is (CF) lung fibrosis cystic in in decline therapies mucoactive of goal The Background: Abstract 2021 11, July 6 5 4 3 Italy Milan, 2 1 specialists Italian of Pappagallo Audit Giovanni an Volpi fibrosis: Sonia cystic in alfa dornase of Use RC ` rnaOpdl agoePlciioMilano Epidemiologist Private Policlinico Maggiore Ospedale C`a Granda II IRCCS Federico Naples of Italy University Naples, II”, Center, ”Federico Fibrosis University Cystic Policlinico, Maggiore Ospedale Granda Ca’ IRCCS Verona Fondazione Integrata Universitaria Ospedaliera Azienda 3,4 . 1 icnoCarnovale Vincenzo , 6 hrfr,ms ainsrqiemcatv gnsadadtoa hrpuisthat therapeutics additional and agents mucoactive require patients most Therefore, . 6 2 7 al Colombo Carla , yrlzn h N nC ains uu n euigsputum reducing and mucus patients’ CF in DNA the Hydrolyzing . 1 3 aei Raia Valeria , 4 rnec Blasi Francesco , 1,2 hsmyinduce may This . 5 5 . and , Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. edo Fmngmn nIay(.Opdl iieS ieaoe ti .Opdl a al iPotenza; Di Carlo San the Ospedale in 2. practice Atri; clinical Liberatore, S. the Civile of Ospedale representative (1. as Italy Centers in specialized management 16 CF of from field selected were experts Nineteen specialists CF of Panel following the medical into divided in statements involved 11 specialists defined committee of steering representative scientific topics: as The main institutions, CF. seven with Italian patients among of identified care meeting. were consensus experts final statement of (v) Six online results; then (iii) the specialists; and of of literature committee analysis panel steering the and expert Scientific reviewing collection an scientific of (iv) of a preliminarily selection expert; of (ii) charge each establishment ranked; by in (i) be ranking were steps: to who following statements the experts the by developing study. six By months the of seven experience. in committee nearly involved individual over steering be and developed of evidence health-related was in consented both within process anonymously participant to uncertainty The questionnaires each according of questionnaire, structured consensus area the of group an given returning series reliable a used and a most in completing we anonymously the experts patients, complete reach of to CF to panel have order for a experts alfa of The dornase opinion research. with of therapy convergence of the (Estimate-Talk-Estimate) verify appropriateness method the Delphi-based on online consensus the assess To pulmonary international the Methods of 2. recommendations and function with lung alignment improve to in alfa CF, dornase practice. are with of guidelines. clinical use people experts CF appropriate international in most CF in the the outcomes Italian agents promote within long-term to mucolytic the discussion was of how goal global final prescription of the our the expand evidence Therefore, influence to the contribute that Indeed, may factors appropriateness United alfa on on patients. dornase in community Centers CF of scientific CF 62% for multicenter use Italian and this alfa the from of with Italy dornase specialists aim dealing of among in the consensus use areas, 33% of geographic therapeutic were level different of the patients, in investigate use CF to alfa shows all was dornase (ECFS) work of in scenario Society seen current Fibrosis the alfa, the Considering Cystic dornase Indeed, European of Europe. the rates in of use agent some mucoactive the report Kingdom and this 2017 data Sweden of Spain, in Annual Italy, use that Registry lowest countries. Patient the European in with recent time countries 2017 most of among was in period are alfa (87%) same countries, dornase CF the Registry, eastern with in Patient observed individuals (CFF) those Foundation of than Fibrosis majority higher Cystic vast the CF the to by for according used prescription States, its main United in the the by countries In managed between databases practice. exist CF, clinical differences for current significant therapies in that recommended treatment show the Societies in the alfa Fibrosis decreasing dornase Cystic and of function inclusion lung the in Despite decline the exacerbations reducing pulmonary in of effective number is agent mucoactive this viscoelasticity, Pyiteaitsrl nmngn therapy managing in role adherence Physiotherapist’s therapeutic 7. improve agents to mucoactive Strategies with 6. therapy of agents Manageability mucoactive agents benefit 5. choosing mucoactive clinical for with of Criteria treated indicative be 4. outcomes agents to of mucoactive patient Definition with pediatric treated 3. the be of to Identification patient 2. the of Identification 1. 10 . 8 . 2 11 hsi ru-aiiaiemto eindto designed method group-facilitative a is This . 9 hs s ae fdraeaf r much are alfa dornase of rates use These . Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. notogop,toewt iwyiflmainadtoewtot Fptet ihiflmainwere inflammation with patients CF divided were without. patients those lavage, and bronchoalveolar inflammation initial airway an with on those Based groups, two effect. into anti-inflammatory potential this admzdtilicuig15C ainswt idln ies (FEV CF, disease CF with lung patients in mild of inflammation with fluid airway patients BAL on CF in agent 105 metalloproteases mucoactive including on this inflammation effect trial of of beneficial randomized impact markers a positive on exhert the effects to supporting positive shown shown was also alfa has course Dornase and increasing the process in an early is disease used there the when destruction, of progression lung components disease irreversible slow to of to treatment disease driver effects a a of anti-inflammatory patients as with as CF process therapies in proposed high inflammatory in airways the interest been of obstructed of has Reduction from role alfa clearance the obstruction. mucus dornase Given improve further using and producing by viscosity and fragments mucus mucous the smaller reduce of into neutrophil- viscosity DNA and weight the infection, molecular increasing obstruction, of actin, first cycle and continuous the DNA a at by patients characterized inflammation is CF dominated CF in of agents pathophysiology mucoactive The of statement. use this the to involvement starting response pulmonary on consensus of inflammation, process. reached of evidence infectious control panel indirect the through of expert function consequently, The lung and, in accumulation decline mucus the of slow reduction or agents with prevent mucoactive to order with in treated involvement be to 1 for re- patient alfa, Statement statements the dornase 11 of including the Identification agents, of mucoactive 1: each of TOPIC for process patients. disagreement prescribing CF or the of agreement management to rated the related performed issues specialists different garding CF statement of agreement. each 80% on panel opinion [?] The at their defined express consensus to Results final the order with of 3. in 2=no) members used (1=yes, six and the options method plus meeting response specialists), Conference two web Development CF using a (28 Consensus attended panel the expanded committee, on an steering based survey, was online anonymous project and the individual of phase 7. final to The equal or greater meeting was consensus score Final median the if appropriate considered be atcpnsepesdterlvlo gemn nec ttmn sn h ADnn-on cl (ranging scale nine-point RAND the using statement each on committee meeting. agreement steering from consensus of final scientific level secured the their The a expressed to Team”. on Participants prior “Pulmocare online results performed platform: the was dedicated analyzed survey agreement and online The rated blindly. collected an who and using experts independently panel website, them, to survey of delivered each were committee for steering disagreement the or by developed G. statements 11 Istituto The 16. Milano; Policlinico, ranking di statement Maggiore Studi Online Universit`a Ospedaliero Alto degli 14. Presidio Ospedaliero Pediatrico; 15. Presidio Centro Napoli; 12. Genova). - AOU, Gaslini, Firenze; Verona Meyer, II” Maggiore, “Federico Azi- Ospedaliera Civile Dei 8. Napoli Azienda Ospedale Ospedale Pediatrico Ancona; 10. 13. 11. Ospedale Messina; Salesi, Palermo; Gubbio; di G. Chiascio, Cristina, 5. Universitario Ospedaliero Di Ospedale Parma; Presidio 9. G. di 7. Orbassano; Bambini Ospedaliero-Universitaria Luigi, Roma; S. Azienda I, Ospedaliero-Universitaria Umberto enda 4. Policlinico Terme; 6. Ges`u, Lamezia Roma; Bambino Di Ospedale 3. 1 = 16 opeeydisagree completely ons lahswl-ouetdbnfiilciia ffcso h btuto n infection and obstruction the on effects clinical beneficial well-documented has alfa Dornase . ramn ihmcatv gnssol epooe ttefis vdneo pulmonary of evidence first the at proposed be should agents mucoactive with Treatment : 14 nadto,ncoi fnurpislast h cuuaino extracellular of accumulation the to leads neutrophils of necrosis addition, In . to 9 = Fgr 1A (Figure opeeyagree completely .I nlcnessmeig hr a ounanimous no was there meeting, consensus final In ). 3 n osnu a ece htasaeethdto had statement a that reached was consensus and ) 1 > 0 rdce)demonstrated predicted) 80% 17 npriua,a particular, In . 12,13 fe the After . 15 16 . . Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. hc ersn h anotoe o salsigteciia ffcieeso uocieteais( therapies life mucoactive of of quality effectiveness and clinical the exacerbations establishing pulmonary for of 2 quality outcomes frequency and main function, the exacerbations respiratory represent pulmonary which assess of to frequency suggest patients, function, CF pulmonary include life. CF this of with of patients results in benefits The therapy clinical 0.048). of CF 4 indicative = with exacerbations Statement children outcomes P respiratory in of 0.66, of approach Definition intervention risk risk early (relative The 3: an alfa TOPIC 0.006). of a FEV dornase = importance for had receiving the (P benefit patients placebo support predicted treatment in receiving trial 1.2% the two-year 34% patients +- Thus, by whereas 3.2% predicted. reduced was predicted), 0.8% was alfa 0.8% +- dornase 3.2% +- received of 0.04% who baseline SE, of from risk +- decrease the baseline mean reduces from and function change mild lung with (mean patients maintains CF therapy young this in that in exacerbations alfa demonstrated alfa dornase abnormalities dornase of sensitive function from trial spirometry a lung effect placebo-controlled normal is treatment randomized, and two-year significant (LCI) disease a a index Importantly, lung detect self- clearance mild to lung that with able docu- events cohort the was changes pathological pediatric that that a pulmonary of demonstrated measure on early cascade collaborators outcome act the responsive of and to and anticipating Amin presence order in obstruction, CF. the important and in in is maintains inflammation early disease, therapy of disease lung mucoactive component pulmonary the of of the starting evidence evidence examinations, without instrumental without by children CF mented level in in with CF high prescription of children the agent progression In statement, mucoactive the in the this in inflammation of shown to airway appropriateness as of response the role CF, unanimous regarding with no aspect patients was this pediatric on there reached meeting, agreement consensus pulmonary of of final tests in or imaging Although by documented abnormalities LCI. pulmonary agents early including mucoactive of function, presence with the treated in considered be be to patient months 3 six pediatric Statement of the trials trials of in in exacerbations Identification CF pulmonary 2: showed with in decrease TOPIC people clearance, a in airway to function led on lung and impact years improved longer two positive alfa or to to dornase a month alfa one with have from dornase therapy that lasting comparing placebo, medications trials with other controlled compared or quasi-randomized that and therapy mucoactive statement. randomized standard this of of placebo, for use review response the Cochrane unanimous recent for no A marker was there a meeting, considered consensus is final exacerbations In of frequency the ( that dornase therapy shows with it disease. treated as lung not relevant patients of in exacerbations year monary per had drop 2: all predicted Statement baseline 3.26% at a inflammation FEV to have patients compared not treated did as alfa1 in who year, addition, patients In per no and number. follow-up. predicted was alfa neutrophils on there inflammation and dornase alfa, levels neutrophilic with dornase worsening IL-8 treated with and treated not elastase patients patients by In CF measured not. as or responses alfa inflammatory dornase in with change treatment to randomized then ) 22,23 7 . h tla xet nC,i gemn ihtems eetgieie ntemngmn of management the on guidelines recent most the with agreement in CF, in experts Italian The nfia osnu etn,teewsuaiosrsos oti ttmn.TeNC guidelines NICE The statement. this to response unanimous was there meeting, consensus final In . 18 iue1B Figure . 21 ncide ihC ihu vdneo ugdsae ramn ihmcatv gnsshould agents mucoactive with treatment disease, lung of evidence without CF with children In : h anotoe ob vlae nodrt sestebnfiileet fmucoactive of effects beneficial the assess to order in evaluated be to outcomes main The : r amn ihmcatv gnssol epooe nptet ihC ihfeun pul- frequent with CF with patients in proposed be should agents mucoactive with Treatment t9 ek,ptet rae ihdraeaf anandFEV maintained alfa dornase with treated patients weeks, 96 At . ). h opeeareeto h xetpnlo hssaeetis statement this on panel expert the of agreement complete The iue1C, Figure 4 a erltdt h motneatiue othe to attributed importance the to related be may 20 . 1 tterbsln value baseline their at 1 rpe y1.99% by dropped 21 . 1 npatients in Figure 19 . 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Data may be preliminary. nraigsl ocnrtoso h uia ieo h eprtr pteimi huh ohdaethe hydrate to chloride. thought sodium is 7% epithelium to respiratory 3% the of of concentration side a luminal bacteria at infecting the which available of on is neutrophils lumen concentrations treatment by airway salt CF the released Increasing clear in DNA to saline down attempt hypertonic breaking fruitless Nebulised patients. by a CF in sputum benefit airways of to infected shown viscoelasticity into been the flood all reduces have agent, mucolytic agents, alfa a hyperosmolar Dornase alfa, both Dornase mannitol, hyperosmolar. and or saline action mucolytic hypertonic either of categories, and mechanisms two into different fall the drugs Mucoactive of light in statement. statement considered this be ( this for agents should on mucoactive alone also different solution the consensus hypertonic of reached or experts solution CF hypertonic Italian and function alfa lung dornase reduces of alfa combination dornase the that suggests 7 database Statement severity. large disease a of of regardless analysis patients an decline in from improvements exacerbations evidence care, demonstrated pulmonary addition, of Studies alfa in In standard dornase reduction evidence. on a is available and CF document of function in review (ECFS) lung efficacy systematic Society in proven a CF has performing European that after the agent conclusion of degrading mucus version only recent the most agent mucoactive the appropriate to most According the as ( statement. alfa disease this dornase lung for of of response choice evidence with the patients on function. CF also lung in consensus of reached stabilization/improvement experts long-term The achieve age to to order according of addition, in patients In action agents, CF mucoactive other. for of each recommended modes replace 6 be cannot that should Statement drugs concluding agent two mucoactive CF, the any therefore for of and therapies use differ detail alfa the dornase in and which reviewed saline clearance document hypertonic muco-ciliary adhesiveness consensus the mucus by promote European and and A mucus viscoelasticity of decision mucus the by properties the of the both in action modify impaired factors to is of key able are mechanism are conditions the drugs clinical Mucoactive Therefore, patient’s and CF. the action ( of and CF of age cascade in mechanisms the pathogenetic making different with by the together characterized of agent are mucoactive therapies. levels mucoactive drugs various different mucoactive between conditions. at different choosing clinical intervene for that patient’s criteria agree the main did the and on agent Experts consensus mucoactive reached of panel expert action The of mechanism the age; patient’s the agents 5 mucoactive disease, Statement of choosing progression for the Criteria document to 4: therapies, new TOPIC of practice effects clinical the assess CF inform to with to trials patients and quality clinical for related in health utilized designed be poor specifically fully may to HRQL be related of been not measure have may outcome months 6 (HRQL) and past patients life the CF of in exacerbations of pulmonary lifetime and the function throughout events critical reversible are also should exacerbations events adverse Pulmonary and exacerbations for antibiotics for considered need be the markers, inflammation that indicate 33 . 24 rqeteaebtosaeascae ihaclrtddciei ugfunction lung in decline accelerated with associated are exacerbations Frequent . 22 h anciei o udn h hiebtentedffrn uocieaet hudbe should agents mucoactive different the between choice the guiding for criteria main The : nC ainswt ndqaersos ritlrnet ons lateay h s of use the therapy, alfa dornase to intolerance or response inadequate with patients CF In : nC ainswt vdneo ugdsae ons lasol epeerdt other to preferred be should alfa dornase disease, lung of evidence with patients CF In : 25-27 . iue3A Figure h ytcFboi usinar-eie CQR savldtdptetreported patient validated a is (CFQ-R) Questionnaire-Revised Fibrosis Cystic The . .I nlcnessmeig hr a nnmu epnet hsstatement. this to response unanimous was there meeting, consensus final In ). 28 . iue3C Figure iue3B Figure .I nlcnessmeig hr a nnmu response unanimous was there meeting, consensus final In ). 5 .I nlcnessmeig hr a unanimous was there meeting, consensus final In ). 30 28,29 . hsdsaeseicinstrument disease-specific This . 32 h uhr ece this reached authors The . 31 . 25 34 orlung Poor . . . 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Data may be preliminary. hr a nnmu epnet hsstatement. this important ( very patients to a CF response represents in which unanimous therapies adherence was from therapeutic there effects sustain patients, to beneficial CF necessary achieving is in in it adherence factor that therapeutic agreed to experts barriers CF needs specific All specific the on identify based strategies to important intervention is planning it Consequently, more pies. play adherence 9 requirement therapeutic Statement time improve to and Strategies burden 6. treatment TOPIC minimum alfa adherence therapy, dornase medication with alfa in rare roles dornase are not important of symptoms is irritative tolerability it addition, mannitol, In Good and and tasteless. solution alfa. completely day administering hypertonic dornase is with a before of drug common required use once the very are the is and administered during which which is cough, reported protection of never alfa pharmacological therapy onset is or dornase than The test therapy Indeed, agents. alfa pre-use mucoactive other dornase a patients. of perform CF management to better by necessary a solution to benefit hypertonic contribute may factors with children several young practice, and clinical infants that In RCTs previous from off-treatment therapy evidence in this the as from support treatment and during complications patients outcomes older typical serious as were other SAEs or these hospitalization the of periods in by most resulting classified events and were adverse alfa of up of dornase ERCF out follow Twenty-eight to ERCF The CF related total 2000. age. of and during possibly of of 1994 occurring as years analysis between (SAEs) 5 clinics good enrolled safety events under participating are were adverse children comprehensive groups who serious and a age patients (0.18%) infants 15,979 project, all 15,865 on on (ERCF) in placed data was drug Fibrosis contained Emphasis the Cystic database performed. of of was profile Registry from alfa safety benefit Epidemiologic dornase and alfa the tolerability dornase of using the patients tion that adherence. CF and medication that of use confirmed question registries its the from and raises originating daily CF studies require Observational that of therapies burden of life-long multiple treatment profile needs The tolerability and disease well-known administration. progressive the time-consuming and chronic to a correlated is fibrosis be Cystic to has statement ( this alfa on dornase reached consensus high The adherence. therapeutic on impact positive potential agents six mucoactive 8 than with the Statement CF. earlier therapy guiding with choose of not patient to Manageability each place help for 5: take will agents TOPIC monitoring must of and combination therapy discussion or both mucoactive agent assessment, and a appropriate Accurate alfa most of initiation. dornase its appropriateness of after CF the that months with of from patients differs assessment in agents clearance Careful mucus hyperosmolar improving of in action complementary airways of are obstructive approaches mechanism other the and an CF conclusion, creating in In clearance by airways mucociliary increase the to into shown water been diseases draws has inhaled, and when gradient therapy, osmotic function hyperosmolar lung alternative hence an and Mannitol, clearance mucociliary improving thereby mucus, viscous 39 41 ainsudr5yaso g h eetetdwt ons laeprecdasmlrfrequency similar a experienced alfa dornase with treated were who age of years 5 under Patients . 37-39 hs eut niaeta Fptet ne er faetlrt ons laa es swell as least at alfa dornase tolerate age of years 5 under patients CF that indicate results These . . : iue4 Figure deec orcmeddtetetrgmni rca oesr h ffcieeso thera- of effectiveness the ensure to crucial is regimen treatment recommended to Adherence : ons lateayhsipratavnae ntrso adigadtlrblt,with tolerability, and handling of terms in advantages important has therapy Alfa Dornase 42,43 . .I nlcnessmeig hr a nnmu epnet hsstatement. this to response unanimous was there meeting, consensus final In ). 44,45 . 6 . iue5A Figure .I nlcnessmeeting, consensus final In ). 31,35,36 40 . . 41 fe comple- After . 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Data may be preliminary. h nig fa tla uvyidctdta hsohrpsspa e oei h aeo tla CF Italian of care the use in their to role families key and a patients play educating physiotherapists and that therapies often indicated therapies. inhaled who survey to performing patient Italian related by the uncertainties patients, an for and and of doubts clinician findings the reporting The standards appropriate for in these an both uninhibited maintain with interface to more levels physiotherapists valid and staffing by a freer adequate represents for feels be physiotherapist cared should The there be and care. should management of patients CF CF in expertise that of opinion level physiother- CF widespread the now for of is responsibility program the It rehabilitation clinician. also the respiratory is ( just which The statement of not management this statement. and the apist on this therapy, aerosol panel to includes expert response often the patient.patients unanimous by individual was the reached there for was strategy meeting, consensus therapeutic appropriate high most very the A define to order in team multidisciplinary therapy the 11 by managing Statement change in towards role move Physiotherapist’s and 7: behaviours TOPIC and beliefs between strategies discrepancies listening developed active explore style using to counseling patient-centered patients behavior a CF change as support patients 1983, help in social to described specifically first or was psychiatric, (MI) interviewing models financial, Motivational desirable as as viewed assistance such being for increasingly worker adherence, are care. social management the team of and or to consultations psychologist, to a Indeed, barriers approaches CF to collaborative time families. reveal referral burden. their require and may treatment may and burden that dialogue patients reducing stressors treatment with and honest where relationship care and collaborative condition simplifying supportive, open on a a focus in establish should that should interventions specialists mindful any is be huge, professional are should health respect pressures and clinicians mutual patient and adherence between communication enhance relationship good To the for fibrosis, allow cystic should as to and such relevant strategy disease extremely a complex as very interview a motivational In the of use the statement. on this consensus ( to fibrosis of cystic level in high adherence a enhance reached support panel adherence expert tailor The to order management in disease consequently, differences and, these of 10 aware that Statement intervention be all to fits of need developing one-size issues clinicians including of simple and appropriately adherence no process affecting effective, is the issues there be different Consequently, in can have opportunity. conditions. people step and different long-term capability, crucial of that motivation, self-management a emphasizes support study is recent to interventions adherence A change control, affecting behavior of evidence-based factors perceptions effective identity, the professionals person’s health understanding a the therapy, with having Completely do interaction burden, to and treatment forgetting knowledge of routine, and extent a support, the having social by treatment, influenced CF do is in to regimen time outcomes treatment clinical recommended adverse to with Adherence associated from is ranging medication low, to remains Despite adherence CF Poor with exacerbations. individuals pulmonary among pre- prevent adherence are 76% and medication to inflammation function treatments, 33% and CF lung infection improve of control benefits to to the therapies and maintenance clearance as mucociliary scribed augment to therapies Mucoactive 46-48 52 hsohrps ihaseicepriei eprtr eaiiainsol epr fthe of part be should rehabilitation respiratory in expertise specific a with physiotherapist A : . h oiainlitriwwt ainscudb sdt mrv hrpui adherence therapeutic improve to used be could patients with interview motivational The : deec fC dlst eiainrgmn a endcmne sproblematic as documented been has regimens medication to adults CF of Adherence . 56,57 . iue5B Figure . 55 lncasadohrhatcr rfsinl rciigMI practicing professionals healthcare other and Clinicians . .I nlcnessmeig hr a nnmu response unanimous was there meeting, consensus final In ). 7 52 . iue6 Figure 51 53 . . .I nlconsensus final In ). 54 Patient-centered, . 58 otphysical Most . 49,50 . Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. l uhr otiue qal oti eiwb rtn h etadpouigproa aaadillustra- and data personal producing and text the writing by review this to tions. equally contributed authors All S.p.A. Roche and statement s.r.l. contribution Italia Author Mylan by outside supported years was three work last This the in Vertex and Mylan, Funding Chiesi, for: consultant Vertex, a work. from as submitted fees fees the personal Guidotti, personal work. Zambon, reports from submitted from Volpi the fees fees Dr fees outside personal personal personal years Mylan, Pfizer, fees Grifols, three from from last personal fees from fees personal the and fees personal Menarini, in grants from personal and Bayer, fees grants GSK, personal from Novartis, and from grants from grants fees AstraZeneca, INSMED, from from personal fees fees and personal personal grants and Chiesi, grants from conflict reports no Blasi have they Dr. that declare Raia, Valeria interest. Colombo, of Carla Carnovale, an Vincenzo develop Pappagallo, and Giovanni patient with interest discuss of also Conflict specialists should of team group care multidisciplinary CF therapeutic DECLARATIONS a appropriate The him. by most for the out plan patient. define carried treatment to individual appropriate be order the in should for rehabilitation patients respiratory strategy CF of physiotherapist of a care including medications. the choose mucoactive help of possible, on will combination impact When fibrosis or positive cystic medication patient’s potential with mucoactive individuals a CF appropriate of with tolerability, monitoring most the alfa and and the of assessment dornase handling more Careful addition, of regardless be In adherence. terms should benefits therapeutic in function. alfa advantages lung therapeutic patient dornase important of significant the features, has stabilization/improvement unique of therapy long-term has its enables conditions alfa to and clinical severity lung Due dornase the disease agents. age, early consideration, mucoactive the establish into of consider action taken to to of important treatment effort mechanism is timely the concerted it start and agents to a mucoactive and making selecting children When of in tests importance function the agents. pulmonary mucoactive sensitive stress with lung and we in imaging decline by setting, the abnormalities slow pediatric mu- or prevent with exacerbations. the to patients pulmonary In order of CF in number treating involvement the pulmonary suggest decrease of we and evidence management, function first CF the its on at regarding agents guidelines CF scenario coative international in varied alfa with current dornase agreement the of In influence use that the factors optimizing centers. of at CF aimed analysis in work the use multicenter from Italian starting an practice of clinical result the side-effects is document physical This disease, of severity age, Conclusions his conditions 5. of domestic and consideration social with and patient, complications, individual patient as or the ageing fibrosis the to cystic by tailored of experienced care be comorbidities respiratory or care the complications of in of involved standards management physiotherapists ECFS of the role in caregivers the outlined with and coherent patients are to data demonstrations These hands-on provide and participate actively therapists 59 h Fpyiteaitsol loipeetsrtge o the for strategies implement also should physiotherapist CF The . 59 8 . 59 l nevnin should interventions All . 58 . Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. iwyiflmaini ainswt ytcfirss mJRsi rtCr e 2004;169(6):719-25. on Med alpha Care for dornase Lavage Crit Bronchoalveolar Respir with al; J treatment Am et of J, fibrosis. Effect Shute cystic D, with Group. Worlitzsch patients Study M, in Treatment the Griese inflammation in airway Antiinflammatory M, role of Ballmann potential Evaluation E, function: Rietschel the lung 2012;11(2):78-83. K, and Fibros Paul inflammation Cyst on 17. J alfa fibrosis. dornase of cystic of use of Effect the treatment F. in early Ratjen 2010;45(12):1167-72. Trends MW, Pulmonol Fibrosis. Konstan Pediatr Cystic 16. 1995-2005. of Advisory fibrosis: Scientific Study al; cystic Epidemiologic et in the WJ, therapies Morgan of A, routine Yegin Coordinators DJ, and Pasta Investigators Chest L, Rasouliyan Clin Group; DR, VanDevanter fibrosis. development MW, cystic Konstan Consensus for 15. Policy1999;4(4):236-48. therapies al. Res anti-inflammatory et Serv and Jun;28(2):331-46. Health J, Inflammation 2007 J Askham MW. Med. guidelines. C, Konstan clinical JF, Sanderson creating Chmiel M, in 14. practice McKee use. best D, for of Lamping guidelines review M, and a Murphy characteristics methods: N, methods: Black Consensus (9):979-983. RH. 13. 1984;74 Brook Health 2003;103:7-16. M, Public Educ Chassin of 2019. Health J, Journal al, research. Kosecoff American et health A, J and Fink Rens method van 12. Delphi L, The Naehrlich J. A, Meyrick Orenti De A, 11. Zolin 2018, Registry. Report Patient Annual Foundation ECFSPR Fibrosis 1994;331(10):637-42. 10. Cystic Med 2017 J Engl Report aerosolized N Data of Annual patients Group. Effect in 9. Study function al. Pulmozyme pulmonary et on The BW, and Ramsey fibrosis. symptoms ML, respiratory cystic Nash of with EM, exacerbations Morris on patients DH, DNase of Christiansen human recombinant DS, management Borowitz the HJ, Fuchs in (rhDNase) 8. deoxyribonuclease 2008;2(4):611-7. human Biologics Med. recombinant fibrosis. BMC of cystic disease. Review with respiratory T. fibrosis Pressler cystic treating 7. in progress of 1993;341(8852):1065-69. Pt State DR. (8 Lancet. Devanter 2012;10:88. 2001;164 Van fibrosis. PA, cystic Flume Med. cystic of Care 6. with Pathogenesis children Crit N. Hoiby in Respir C, inflammation J Koch Airway Am 5. FJ. induction. Accurso sputum MK, by Sontag assessed I, 1):1425-31. children (5):356-66. Osberg healthy 2001;32 infection, R, and Pulmonol pulmonary Kapsner Pediatr Early fibrosis SD, al. fibrosis. Sagel et cystic R, with Castile 4. infants JL, in Burns cystic J, outcomes the Emerson clinical of S, and Identification McNamara RL, inflammation, (4922):1059-65. al. Gibson 1989;245 et M, M, Rosenfeld Science. Dean 3. G, jumping. Melmer and ML, cystic walking Drumm the chromosome B, of (4922):1066-73. gene: Kerem Identification 1989;245 MC, fibrosis al. Iannuzzi Science et JM, DNA. Z, Rommens complementary Grzelczak 2. R, of Rozmahel characterization N, and Alon cloning B, Kerem gene: JM, fibrosis Material. Rommens Supplementary JR, the Riordan as in 1. statement listed each are rated TEAM and PULMOCARE meeting of Atorino, web References specialists Luigia the CF of attended 28 that The support TEAM Panel. helpful PULMOCARE Expert S.p.A. the the Roche thank with and authors SpA, s.r.l The Italia EDRA Mylan by by provided supported was and PhD, assistance editing and Writing Acknowledgements 9 Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 5 akP,MDnl ,JnsA.Nblsdhproi aiefrcsi boi.Ccrn Database Cochrane fibrosis. cystic for saline hypertonic Nebulised (3):CD001506. (2 AP. 2005; 1995;107 Jones Chest Rev. V, Syst fibrosis. McDonald cystic PA, Wark of treatment alfa 35. the dornase for of practice 1 use DNase Clinical best human al. recombinant ECFS Suppl):65S-70S. et Aerosolised A, a; S. Yegin FEV Shak et JR, of 34. Jacobs F, rate SJ, slower Ratjen Millar a A, DJ, with Pasta Munck associated JS, is Wagener HGM, MW, 2018;17(2):153-78. Heijerman Konstan Fibros SC, Cyst 33. J Bell revision. AJA, 2018 Fibros Duff the Cyst J C, guidelines: consensus. Castellani European A 32. mucociliary fibrosis: cystic of medication Inhaled with study patients group. the in working disease consensus for 2009;8(5):295-315. G; lung model Doring for D, devices Touw a S, inhalation Conway as and E, Westerman palate H, frog Heijerman Mucus-depleted 31. manual. 1990;69(2):424-9. M. user’s Physiol. King (CFQ): Appl O, questionnaire J Ramirez fibrosis clearance. BK, cystic Rubin The MA. cystic 30. Davis 2000. the Foundation; M, of Watrous Fibrosis validation Cystic A, Chest DC: and Buu Washington, fibrosis. Development AL, cystic Quittner M. for Watrous measure factors 29. AC, quality-of-life of health-related Modi a review MS, States: systematic Messer United 2005;128(4):2347-54. A the A, Thorac in BS. Am Buu questionnaire Ann Quon AL, fibrosis fibrosis. JA, Quittner cystic Buxton with 28. adults AR, and Javer adolescents PG, in Mar;12(3):420-8. life Wilcox 2015 of Soc J, quality health-related Manji global with on AR, impact associated Habib fibrosis: cystic with (5):324-31. Living 27. 2005;34 T. Lung (1):64-72. Moum Heart 121 E, Gjengedal 2002; life. BR, Chest of Hanestad quality T, fibrosis. Rustoen cystic AK, pulmonary with Wahl recent patients Pulmonol of 26. Impact in Pediatr RW. Wilmott life J, of Tsevat associ- fibrosis. HD, quality Atherton are cystic RW, on Hornung exacerbations with exacerbations UR, Kotagal children Pulmonary MT, Britto and CH. 25. adults Goss both GJ, in Redding decline M, FEV(1) Rosenfeld 2011;46(4):393-400. pond. subsequent RC, the with Bittner across ated DB, outcomes Sanders fibrosis cystic 24. Comparing RL. Smyth MS, 2015;70(3):203-4. Schechter Thorax DC, Trial Taylor-Robinson https://www.nice.org.uk/guidance/ng78. Intervention at 23. Early Avialable Pulmozyme [NG78]. on guideline young abnormalities. alfa NICE in function dornase Early 22. alfa Pulmozyme 2001;139(6):813-20. lung of dornase al; Pediatr of mild effect et J trial with The PJ, Group. placebo-controlled Robinson fibrosis Study randomized, MD, al. cystic two-year Montgomery et with A SG, R, patients McKenzie Group. JP, Jensen Sy Study S, 2011;37(4):806-12. Trial HA, Balkovec Intervention J Tiddens alpha. Respir JM, A, Eur Quan dornase Jabar fibrosis. 21. with W, cystic treatment Lou with patients of P, in 2018;9 influence Subbarao inhomogeneity R, Rev ventilation disease: Amin Syst lung early Database 20. concentrations with DNA Cochrane W. patients Nikolaizik 2005;39(1):1-4. fibrosis E, Rietschel Pulmonol fibrosis. cystic S, Pediatr Breitenstein fluid cystic S, Koningsbruggen BAL van for in K, Paul alfa F, Ratjen Dornase 19. M. Montgomery C, (9):CD001127. Yang 18. 1 eln ncsi boi.PdarPloo 2011;46(6):545-53. Pulmonol Pediatr fibrosis. cystic in decline 10 Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 3 aik S elrK,Dmr ,Rbno M oiaigahrneaogaoecnswt cystic with adolescents 2015;50(2):127-36. among Pulmonol adherence Pediatric Motivating WM. perspectives. Robinson parent N, and Demars Youth KS, Framework.fibrosis: Heller Domains GS, Theoretical Sawicki with the adults 53. and in medication between data 2019;24(2):357-80. to Psychol adherence association Adherence Health objective M. J Longitudinal 2011;10(4):258-64. using Wildman Br M, investigation Fibros KA. Hutchings An Cyst A, Riekert J O’Cathain Fibrosis: S, PJ, fibrosis. Cystic Drabble cystic Mogayzel MA, with Arden MP, people 52. Boyle in health A, lung fibrosis. Bilderback and cystic adherence in MN, outcomes medication Eakin health lung on 51. adherence (6):687-91. medication 2013;19 System of Med Database impact Pulm The JBI with Opin KA. adults Curr Riekert review. of MN, systematic Experiences Eakin qualitative al; 50. a et CM, regimens: 2016;14(5):258-85. Godfrey medication Rep LJ, to Implement Smith Rev adhering M, data. in Helwig therapies hospitalization fibrosis R, long-term and cystic Martin-Misener to M, dispensing, Adherence Macdonald al; prescribing, et 49. linking A, study Denis P, 2019;13:1497-1510. cross-sectional Caillet French Adherence AL, Prefer a Dima Patient S, fibrosis: Allemann cystic M, adolescent in and Viprey children H, 2006;38(1):13-17. in Rouze treatment Health to 48. Adolesc Adherence J SZ. fibrosis. Nasr treatment DS, cystic of Streetman with assessment DD, 2006;5(3):177-85. patients multi-method Streetman Fibros A GN, Cyst AL. Zindani J Quittner 47. MH, fibrosis. Wagner cystic D, with Geller adherence children N, Yu medication for 2017;11:691-8. CS, pulmonary adherence Lim and Adherence. AC, knowledge Prefer Modi Patient Patient 46. BS. fibrosis. Quon cystic Rev PG, with Syst Wilcox patients Database JG, adult Cochrane in Kendrick in fibrosis. DNase AH, cystic JC. Lin for Jongste inhalation 45. de alfa dornase WCJ, of (4):183-8. Hop Timing 2003;2 (11):CD007923. PJFM, M. Fibros 2018;11 Merkus Elkins Cyst HAWM, R, J Dentice Tiddens study. E, 44. pilot Wiel a der infants: patients fibrosis van fibrosis 2001;31(5):377-82. cystic M, Pulmonol cystic stable Berge Pediatr in ten study. DNase preliminary human 43. a recombinant tomography years: aerosolized computerized of 5 of Use age efficacy PJ. than Strouse evaluating GM, younger in Sanders of ME, X-rays Hurwitz Registry RW, chest Brown Epidemiologic and LR, the Kuhns SZ, of Nasr should Investigators 42. ME; how 2007;42(10):928-37. Hodson clearance: Pulmonol B, sputum Pediatr Strandvik 2014;20(6):601-6. aid Fibrosis. S, Med Chowdhury Cystic to Pulm SG, drugs Opin McKenzie of Curr armamentarium 41. care? expanding optimize The to used G. Respira- be Stanford they therapies. D, antibiotic Bilton and mucoactive 40. fibrosis: Rev cystic Expert in clearance. interventions its Inhaled 2014;88(6):441-8. D. and tion Bilton mucus K, on Hurt mannitol powder 39. (3):678-85. dry 1999;14 inhaled mannitol J (1):65-75. of inhaled Respir 2013;7 of Effect Eur Med effect BK. study. Respir The Rubin pilot al; E, et a Daviskas SD, patients: Anderson 38. CF HK, Chan hypertonic in J, clearance a of Baker mucus S, Comparison fibrosis: bronchial Ebert al; on cystic E, Daviskas et with M, S, Robinson children Thompson in 37. C, deoxyribonuclease Normand 2001;20(358):1316-21. human M, Lancet recombinant Flather daily trial. R, randomised or Grieve alternate-day B, and Lees saline C, Metcalfe 36. 11 Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 owyS afu-ynI,D iceK rvnkP oeae ,HvrasT ta;European al; et 2014;13 Fibros T, Cyst Havermans J J, Centre. Foweraker Fibrosis P, Cystic the Drevinek for K, Framework Rijcke 1:S3-22. Care: Suppl of De Standards IM, centres: Society Fibrosis Fibrosis Balfour-Lynn Cystic Cystic S, Italian Conway in practice Cystic delivery 59. Aerosol 2016;6:1. in C. Physiother Problems Colombo Arch A, survey. Adherence Brivio national 2013;5(6):475-80. for F, a Res Carta Interviewing Med S, Motivational Clin Gambazza J Pediatr GJ. 58. Professionals. Latchford Healthcare fibrosis. Duff, Training cystic of Aitken Evaluation in J, Fibrosis; problems Alistair adherence for 57. interviewing Motivational GJ. 2010;45(3):211-20. Latchford Pulmonol. AJ, Duff 1983;11:147- Psychotherapy Behavioural 56. drinkers. problem with interviewing 2014;8(2):39- Motivational 172. Dis WR. Respir Adv Miller Ther 55. fibrosis. cystic in therapies inhaled to 47. adherence Enhancing P. Lomas 54. 12 Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 13 Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 14 Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 15 Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 16 Posted on Authorea 11 Jul 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.162602968.80941763/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 17