Definition of sinonasal and otologic exacerbation in patients with primary ciliary dyskinesia - an expert consensus

Background: Recurrent infections of the nose, sinuses, and ears are common problems for people with primary ciliary dyskinesia (PCD). While pulmonary exacerbations in PCD are defined, there is no definition for Ear-Nose-Throat (ENT) exacerbations, a potential outcome for research and clinical trials.

We set up an expert panel of 24 ENT specialists, respiratory physicians, other healthcare professionals, and patients to develop consensus definitions of sinonasal and otologic exacerbations in children and adults with PCD for research settings. We reviewed the literature and used a modified Delphi approach with four electronic surveys.

Both definitions are based on a combination of major and minor criteria, requiring three major or two major and at least two minor criteria each. Major criteria for a sinonasal exacerbation are: 1) reported acute increase in nasal discharge or change in colour; 2) reported acute pain or sensitivity in the sinus regions; 3) mucopurulent discharge on examination. Minor criteria include: reported symptoms; examination signs; doctor´s decision to treat; improvement after at least 14-days. Major criteria for the otologic exacerbation are: 1) reported acute ear pain or sensitivity, 2) reported acute ear discharge, 3) ear discharge on examination, 4) signs of otitis media in otoscopy. Minor criteria are: reported acute hearing problems; signs of acute complication; doctor´s decision to treat.

These definitions might offer a useful outcome measure for PCD research in different settings. They should be validated in future studies and trials together with other potential outcomes, to assess their usability. 246/250 . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 4

Dysfunction of motile cilia due to genetic mutations leads to a wide range of symptoms including multiple organ systems in patients with primary ciliary dyskinesia (PCD).[1, 2] Despite the clinical heterogeneity, the greatest impact of impaired mucociliary clearance is seen on the respiratory tract and the ears.[3] Patients present with persistent wet cough and recurrent lower airway infections, progressing with time to irreversible lung damage.[3] Inadequate clearance of mucus, pathogens, and debris in the nose and sinuses, as well as in the eustachian tube and middle ear, leads to bacteria growing in the mucus-clogged airways. Consequently, patients experience recurrent episodes of sinonasal infections, and the risk of sinonasal disease increases with age, with chronic rhinosinusitis (CRS) becoming a common feature as disease progresses.[4–6] From the ears, recurrent episodes of acute otitis media (AOM) often progress to severe bilateral otitis media with effusion (OME) and conductive hearing impairment.[7–11] Acute infections of the nose, sinuses, and ears in PCD, usually involve already impaired upper airways, with a more complicated pathophysiology and course compared to common acute upper airway infections. Respiratory exacerbations are a significant determinant of morbidity and subsequent care requirements of people with chronic respiratory diseases. They are typically characterised by deterioration of the patient´s clinical condition, most often due to viral or bacterial infections or exposure to other triggering factors. Exacerbations often require additional management and have significant effects on disease progression, severity, and patients´ quality of life.[12–15] For clinical and epidemiological research, exacerbations are important outcomes, in measuring burden of disease or response to treatments.[16, 17] In PCD, pulmonary exacerbations have been defined, and were recently included in a core outcome set for pulmonary disease interventions,[18, 19] in the framework of the BEAT-PCD clinical research collaboration supported by the European Respiratory Society (ERS).[20, 21] The existing definition excluded upper respiratory tract exacerbations because they often occur independently from lower respiratory tract exacerbations and have different prognosis.[18] Therefore, despite their impact on severity of PCD, there is still no definition for Ear-Nose-Throat (ENT) exacerbations. . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 5 This lack is an important gap as clinical outcomes capturing ENT disease in PCD are even fewer than for lung disease.[22] Using an international panel of specialists involved in PCD care, we aimed to develop a consensus definition of ENT exacerbations for children and adults with PCD, participating in clinical research.

Participants and purpose of the consensus We established an expert panel consisting mainly of ENT specialists, with expertise in managing children and adults with PCD. We invited specialists from PCD reference centres in Europe, North America, Australia, and Japan, and encouraged invited participants to suggest further members ensuring wide international representation (Supplementary Table S1). Additionally, we invited a paediatric and an adult pulmonologist, involved in the consensus group of the pulmonary exacerbations definition,[18] and other healthcare professionals involved in PCD patient care and research. The panel was completed by two patient representatives, an adult with PCD and a parent of a child with PCD; 24 members in total, representing 13 countries. To ensure significant patient involvement and input from the people who experience first-hand these exacerbations, we also set up a parallel group of patient and parent volunteers, with support from the European Lung Foundation (ELF),[23] who did not join the consensus panel, but provided feedback and were encouraged to participate in the surveys. The activities of the panel and the patient group were coordinated by two facilitators, a clinical epidemiologist with expertise in PCD research (MG) and a PCD PhD candidate (YTL); the latter did not participate in voting. An initial virtual panel meeting refined the aims and proposed methodology. It was concluded that standardised definitions for PCD were missing and decided unanimously to produce two separate definitions: one for sinonasal exacerbations and one for otologic exacerbations. Our goal was to establish definitions meant to be used in research and clinical practice. Literature search We conducted a systematic literature search of publications referring to ENT exacerbations in patients with PCD, or separately sinonasal and otologic exacerbations. Given the anticipated . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 6 limited pre-existing literature on the topic, our search strategy was expanded at the outset to include other areas with common characteristics, in particular CRS. We searched PubMed for studies published between January 2012 and December 2021 using the following keywords: ciliary dyskinesia, primary OR immotile cilia syndrome OR Kartagener/ AND exacerbat* OR infect* OR acute/ AND sinus* for sinonasal exacerbations, or otit* OR ear or otol*, for otologic ones. We simplified the terms, excluding PCD specific keywords, to expand on other diseases excluding the PCD related keywords. We did not exclude any publication type or language. Reaching a consensus A modified Delphi approach with online (eDelphi) surveys was used. Initial literature search

revealed that identified pre-existing definitions did not cover the need for PCD-specific definitions but should be used as a starting point for the first eDelphi survey. Based on these definitions and the panel consensus, we identified important components for definitions of sinonasal and otologic exacerbations. For each survey, participants received detailed instructions and a link via e-mail, then two reminders to respond within two and three weeks. The panel decided that at least an 85% response rate would be required to proceed to the next survey and that 80% of agreement would signify consensus; however, possibility of accepting lower agreement as consensus was left open provided that the panel would be informed and there would be no veto against it. Each survey (eDelphi survey Supplementary material 1-4) included different types of questions to reach consensus initially on the included components for each definition and subsequently on the details of specific components e.g. elements of included components such as specific symptoms or signs. Each survey was designed based on the results of the previous survey and included a summary of these for the panel´s information. Participants were asked to explain their opinions in free text boxes, particularly where consensus was not achievable despite high agreement, so statements could be clarified and modified in the next round. The number of surveys was not predefined, but ultimately 4 surveys were required. A virtual meeting was organised with MG and the patient group to explain details of the project to the patient or parent members and provide any answers to their questions. Replies remained anonymous to the panel and only the facilitators had access . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 7 to identifying information. After the eDelphi surveys were completed, the results of the final survey were circulated among the panel to ensure all members agreed with the final definitions.

Literature search Our search resulted in total of 2352 abstracts related to sinonasal and 2208 to otologic exacerbations respectively. No abstracts with definitions specific to PCD were identified. After excluding duplicates and screening the abstracts, we identified 24 manuscripts that referred to sinonasal exacerbations. By searching their references 6 additional manuscripts were identified, 30 in total, including one systematic review.[24] A summary of definitions used in literature for sinonasal exacerbation in patients with CRS in the identified studies is presented in Table 1.[24– 53] These definitions were discussed at a virtual expert panel meeting and the elements they used were considered for developing the initial survey. No study fulfilled the criteria of otologic exacerbation of a chronic condition. eDelphi surveys Response rates to the eDelphi surveys ranged between 88 and 100% (Supplementary Table S1). In addition, two to five members of the patient group completed each survey. In survey 1, the panel assessed opinions about the importance of sinonasal and otologic exacerbations for people with PCD and components that should be included in the exacerbation definitions. Consensus was reached that exacerbations from the nose and sinuses are an important problem for both adults and children with PCD, they impact the quality of life of people with PCD and can be an important outcome measure for ENT clinical trials in PCD. For otologic exacerbations, opinions were similar, however no consensus was reached on the importance of this problem for adults with PCD, primarily due to smaller frequency of acute ear exacerbations in adulthood. The panel also agreed that sinonasal, otologic, and pulmonary exacerbations may occur separately from each other, highlighting again the importance of separate definitions. Responses to key questions about the components of the two definitions are presented in Supplementary Table S2. The combination of new symptoms or worsening of baseline symptoms and of new clinical signs or changes in clinical examination was voted as the best . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 8 combination of components to define both sinonasal (93%) and otologic (97%) exacerbations. No consensus was reached about including the following components: 1) changes in imaging for sinonasal exacerbations, 2) decision of ENT specialist to treat (for both definitions), and 3) complete resolution of any changes and return to baseline (for both definitions). Survey 2 included questions on specific elements, particularly symptoms (Supplementary Table S3) and signs (Supplementary Table S4) for the sinonasal and the otologic exacerbation definitions. Agreement was reached for three symptoms and two signs for each definition in this round. Items that achieved 60-79% agreement in survey 2 were discussed again in survey 3. Tables 2 and 3 follow the process of reaching a consensus for the two definitions step by step from survey 2 to survey 4 and the levels of agreement until consensus was reached, or not. Survey 2 also clarified that sinus imaging should not be an absolute requirement for the definition of a sinonasal exacerbation, with main reasoning that it should be restricted for baseline assessment and for complications, and that it entails too much radiation and offers little in case of acute exacerbations (85% agreement). Survey 3 discussed elements from previous surveys, which had scored highly but not yet reached a consensus on inclusion (Supplementary Table S5). The panel unanimously agreed in this survey to introduce major and minor criteria for both definitions. We reached consent (85%) that all clinical signs or changes seen in clinical examinations included in both definitions should be assessed in relation to previous examinations. In survey 4, participants voted if criteria for which consensus was already reached should be included as major or minor (Tables 2 and 3). Criteria that reached more than 50% but less than 80% agreement in survey 3, were now voted upon including whether to assign as minor or exclude. Based on discussions that clinical practice may differ substantially from research practices, particularly in the non-PCD ENT specialist, although we originally considered that the definitions would cover also clinical practice, the panel decided (100% agreement) to include the following clarification: “These definitions are aimed to be used in research settings, especially in clinical trials, to define a sinonasal or otologic exacerbation in patients with PCD”. The panel also agreed that a) 3 major or b) 2 major and at least 2 minor criteria are needed to define a sinonasal or otologic exacerbation (Table 4). For sinonasal exacerbation, we reached consensus . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 9 on three major (reported acute increase in nasal discharge or change in discharge colour, reported acute pain or sensitivity in the sinus region, and mucopurulent nasal discharge at examination) and six minor criteria (reported acute blocked nose or worsening in chronic feeling of blocked nose, reported acute decreased sense of smell, increased mucus production or postnasal drip at examination, signs of acute complication at examination, doctor´s decision to treat, and important improvement in symptoms or clinical findings after a period of at least 14 days). For an otologic exacerbation, we reached consensus on 4 major (reported acute ear sensitivity or pain, reported acute ear discharge, ear discharge at examination, and sign of otitis media in otoscopy) and 3 minor (reported acute hearing problems/worsening in preexisting hearing problems, signs of acute complications at examination, and doctor’s decision to treat). Major criteria were decided on at least 80% consensus and minor on at least 74%, which was agreed in the panel (Tables 2 and 3). Lastly, the panel highlighted that no criterion was an absolute requirement for either definition (Table 4). . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 10 Table 1: Summary of definitions used in litera tur e for sinonasal exac erba tion in pa tients with chr onic rhinosinusi tis Definition References Acute incr ease in severity of sinus diseas e symptoms Armbrust er 2021 Sudden worsening of CRS symptoms wit h a return to baseline symptoms, often a fter treatment Orlandi 2020; Bl eie r 2021 Acute worse ning of pre-exis ting CRS sym ptoms with subsequent return to baseli ne symptoms with or without endoscopi c evide nce Orlandi 2020; Makary 2021 Previous diagnosis of CRS exis ts, and a s udden worsening of symptoms occurs, with a return to baseline symptoms following treatment Orlandi 2016; Philpo tt 2021; Wu 2019; Yan 2018; Barshak 2017 Presence of purulenc e on endosco py du ring a symptomatic ex acerba tion of CRS Orlandi 2016; Vandelaar 2019 Sudden worsening of pre-existing CRS s y mptoms is called a CRS exace rba tion Laulajainen-Honigsto 2020 Diagnosis of chronic rhinosinusitis and ac ute e xacer bati on of CRS according to th e criteria d escribed in the “Europe an Position Paper on Rhinosi nusitis and Nasa l Polyps (EPOS) Fokkens 2020; Yaniv 2020 Previous diagnosis of CRS but wer e ex pe riencing acute exacerb ation of symptoms Fokkens 2012; Ghad ersohi 2020; Kuiper 2018 Acute worsening of sy mptoms with retur n to baselin e, ofte n requi ring a transi ent escalatio n in treatment , such as a course of oral antibi otics or cortic oste roids Fokkens 2012; Phillips 2019; Kuiper 2018; Phillips 2018 Acute exacerba tion of CRS was defined a s having received an a ntibiotic prescripti on for worsening sinus symptoms Kwah 2020 Acute e xace rbat ions among surgically managed CRS patients were d efined as a p ost-endoscopic sinus surgery, afte r 90 days post-op Denneny 2018 Acute bac teri al CRS exace rba tions ( patient-report ed sinus infe ctions and CRS-related antibiotic use ) Sedaghat 2018 Sudden worsening of baseline symptoms (or developing new symptoms ) in a patient with an establish ed CRS diagnosis Lopatin 2018 Sudden worsening of th e baselin e CRS with eith er worsening or new symptoms. Typically, the acut e (not chronic) symptoms resolve compl etely between e xace rbati ons Brook 2016 Worsening , with subsequent resolution , of symptoms in a patient car rying the dia gnosis of CRS Merkley 2015 Defined by minimum SNOT-20 score of 1 .0 on scale of 0 to 5 Jiang 2015 Worsening of symptoms: facial pain or p ressure , nasal obstruction , nasal discharge Rosenfeld 2015; Beswick 2020 Presence of increased nasal cong estion , and facial pain ; increased sinonasal disc harge ; usually presence of an unsch eduled sick visit Zemke 2019, Wu 2020 . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 11 Acute exacerba tion of CRS was defined in a patien t in whom a previous diagnosis of CRS exists, and a sudden worsening of sympto ms occurs, with a return to baselin e symptoms follo wing treatment Orlandi 2016, Wu 2020 Natu ral e xacerb atio n was defined as pati ent-repo rted worsening of sinonasal symptoms (i.e. runny nose, nasal conges tion, a nd nasal obst ru ction) Divekar 2015, Wu 2020 History of sudden worsening of p reexisti ng symptoms suggests an acute ex acerb ation of CRS, which should be diagnosed by similar cri teri a a nd trea ted in a simila r way to acute rhino sinusitis Fokkens 2012, Wu 2020 Self-repor ted medication use (antibiotics and oral cor ticoste roids) for worsened n asal and sinus symptoms ; self-repor ted worsened puru lence in the past 4 weeks Kuiper 2018, Wu 2020 Systemic antibiotics ; systemic corticoste roid; plans for a semi-urge nt surgical int ervention ; emergency depar tment o r urgent care visit , or a hospitalization for CRS Wu 2020 Worse nasal symptoms Wu 2020 CRS: chronic rhinosinusit is, SNOT-20: Sin o-Nasal Ou tcome Test . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 12 Table 2: Process of reaching consensus for the i tems included in t he defini tion of a sinonasal e xacerb atio n. % of agreement Included i n the d efinition (% of agreement) Survey 2 Survey 3 Survey 4 Patient-r epor ted acu te incr ease in nas al discharge or change in discha rge colour 100 - - major criteri on (100) Patient-r epor ted acu te pain or sensitivi ty in the sinus region (i.e . aro und the n ose, eyes, on the che eks or forehe ad) 85 - - major criteri on (83) Patient-r epor ted acu te blocked n ose or worsening in chronic feeling of blocked n ose 92 - - minor crite rion (78) Patient-r epor ted acu te d ecreas ed sense of smell 69 58 74 minor crite rion (74) Reduced quali ty of life evaluat ed by any sinonasal specific quality of life questio n naire 73 50 61 not included Mucopurule nt nasal discha rge at examin ation 100 - - major criteri on (87) Increas ed mucus productio n or post nasa l drip at e xamina tion 92 - - minor crite rion (70) Signs of acute complication (e.g . orbit al i nfection or abscess, meningitis, ce rebr al infection, cranial nerve p alsy) at examina tion 72 52 83 minor crite rion (83) Acute fron tonasal or maxill ary tend ern ess at examin ation - - 65 not included Doctor´s decision to tre at, no t necessa ril y with antibiotics but also with incre ased upper airway clearance o r oth er medica tion 81 - minor crite rion (91) Import ant improvement in symptoms re porte d by the pa tien t or par ent o r in clinical findings in case further e xamina tion is po ssible, after a perio d of at leas t 14 days - 80 - minor crite rion (74) Items th at r eached ≥80% were aut omati cally included in the defini tion. Items t ha t achieved 60-79% agreemen t in Survey 2 were di scussed again in Survey 3. I t e that achi eved 50-79% agreemen t in Survey 3 and newly suggested items by sever al members were discussed in Su rvey 4. At Survey 4, members vot ed whet her i te ms should be considered as major or min or crite rion or b e included a t all. We con sidered r eaching consensus a t ≥80% agreemen t for major crit eria a nd ≥74% for minor crit eria ; items with <74% agre e ment were n ot included at all . . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 13 Table 3: Process of reaching consensus for the i tems included in t he defini tion of an otologic e xacer bati on % of agreement Included i n the d efinition (% of agreement) Survey 2 Survey 3 Survey 4 Patient-r epor ted acu te e ar sensi tivity or pain 92 - - major criteri on (91) Patient-r epor ted acu te e ar discharge 92 - - major criteri on (91) Patient-r epor ted acu te h earing pro blems or worsening in pre existi ng hearing pr ob lems 85 - - minor crite rion (74) Repor ted feeli ng of fullness in the ears 77 58 57 not included Ear discharge at examin ation 92 - major criteri on (83) Signs of otitis media in ot oscopy (i.e. eryt hema, collecti on) 92 - major criteri on (87) Signs of acute complication (mastoidi tis, meningitis, cer ebral absc ess, facial or oth er cranial nerve p alsy) at examina tion 69 46 78 minor crite rion (78) Impaired h earing t est ed by pure-to ne au diometry 69 62 70 not included Perforat ed ear drum at examina tion 62 54 43 not included Horizon tal nystagmus at e xamina tion 35 - 14 not included Doctor´s decision to tre at, no t necessa ril y with antibiotics but also with oth er me dication - 88 78 minor crite rion (78) Import ant improvement in symptoms re porte d by the pa tien t or par ent o r in clinical findings in case further e xamina tion is po ssible, after a perio d of 14 days - 72 70 not included Items th at r eached ≥80% were aut omati cally included in the defini tion. Items t ha t achieved 60-79% agreemen t in Survey 2 were di scussed again in Survey 3. Items th at achi eved 50-79% agreement i n Survey 3 and newly suggested items by several members wer e discussed in Surv ey 4. At Survey 4, members vot ed whet her i te ms should be considered as major or min or crite rion or b e included a t all. We con sidered r eaching consensus a t ≥80% agreemen t for major crit eria a nd ≥74% for minor crit eria ; items with <74% agre e ment were n ot included at all . . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 14 Table 4: Definitions of a sinonasal and an otologic ex acerba tion for childr en and a dults with primary ciliary dyskinesia (PCD ) participating in clinical resea rch I. Sinonasal exacerbation All 3 of the following major criteria or 2 major and at least 2 minor criteria are needed to defin e a sinonasal ex acerbation for children and adu lts with PCD in cl inic al research s ett ings. Major criteria (inc luded based on a t l east 80% consensus): • Patient-reported acu te in crease in nasal discharge or change in d ischarge c olour • Patient-reported acu te pain o r sensi ti vity in the sinus region (i.e. ar ound th e nose, eyes, on the cheeks or fo rehe ad) • Mucopurulent nasal discha rge at exa mination Minor criteria (inc luded based on at l east 74% consensus): • Patient-reported acu te blo cked nos e or worsening in chro nic f eeling of b lo cked nose • Patient-reported acu te dec reased se nse of smell • Increased mucus product ion or pos tn asal drip at examinatio n • Signs of acute complicat ion (e.g. orbit al infec tion o r abscess, meningitis, ce rebral in fect ion, cranial n erve pal sy) a t examination • Doctor´s decis ion to treat, no t necess arily with an tibio tics bu t also wi th inc reased upper ai rway clearanc e or o th er medication • Important improvement in symptoms reported b y the pa tient or paren t or in clini cal f indings in case furthe r exa mination is possible, aft er a per iod of a t least 14 days II. Otologic exacerbation 3 of the following major criteria or 2 major and at least 2 minor criteria are needed to d efine an otol ogic exacer bation fo r child ren and adults with PCD in clin ical r esearc h settings. Majo r criteria ( included bas ed on at l east 80% consensus): • Patient-reported acu te ear s ensit ivit y or pain . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 15 • Patient-reported acu te ear d ischarge • Ear discharge at examination • Signs of otitis media in otos copy (i.e. erythema, collec tion) Minor criteria (inc luded based on at l east 74% consensus): • Patient-reported acu te hear ing probl ems/worsening in preexisting hearing problems • Signs of acute complicat ion (mastoidi tis, meningitis, cerebral abscess, facia l or othe r crania l nerve palsy) a t exa mination • Doctor´s decis ion to treat, no t necess arily with an tibio tics bu t also wi th oth er medication These definitions are aimed to be used in research settings, especially in clinical trials, to define a sinonasal or otologic exacerbation in patients with PCD. No individual criterion is considered an absolutely requirement. . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 16

An internationa l panel o f ENT speciali sts, pulmonologists, healthcar e prof e ssionals, and people with PCD, a greed on consensus de fini tions of sinonasal and otologic exacer bations in ch ildre n and adults with PCD to be used in res earch, especial ly in c lini cal tr ials. This effor t fol lowed similar approach to the one used to d evelop a cons ensus def init ion of pu l monary exacerbations in PCD.[ 18] Although upper and lower airway disease in PCD should be managed in unison and exacerbations often occur s imultaneo usly, or expand to involv e the whole airways, our panel agreed that exacerbat ions f rom the n ose, the sinuses, and th e ears r equire separate definit ions.[54] They can occur indivi dually and have di ffe rent chara cter ist ics. Both ar e an important probl em in children with PCD and whilst in adults sinonasal exac erbations remain a major issue, otologic exacerba tions a re less common. Main strengths of the s tudy were th e internat ional and multid iscip linary na ture of the panel, and the inclu sion o f patien ts and par ents of ch ildren with PCD, together with the added group of patien t volun teers. We perf ormed a thorough systematic r eview of the l i terature, expanding our search also to othe r cond ition s, s uch as o ther types of CRS, which have similari ties with PCD. We retained a high panel re sponse ra te throughout the study. Al though th e panel consid ered originally developing def init ions tha t would also be used for c linica l pract ic e, we agreed during the process that this would no t be f e asible. However simple, clin ical ou tco mes need to be very clearly d efined, whil e for clini cal prac tice a dec ision for an exace rbation might be needed to be taken only based on rep orted symptoms, often without any examination. Our panel discussed tho roughly whet her exis ting defin ition s spec ifica lly fo r exacerbat ion o f CRS, could be used a lso fo r child ren and a dults with PCD, without the ne ed to d evelop dis ease- specifi c defin iti ons. We considered a ll available de fini tions (Table 1), par tic ularly th e lates t European Position Paper on Rh inosin usitis and Nasal Polyps (EPOS) that de fined acut e exacerbation of CRS as worsening of s ymptom intensity with return to base line CRS symptom intensi ty, often a fter inte rvent ion wit h cortic oster oids and or antibi otics.[3 6] We reached consensus that none of them fully co vered the pu rpose o f a PCD-specific d efinit ion, although they highlighted importan t compone nts which we then d iscussed. In part i cular, the panel members agreed on the need to in clu de in the de fini tion PCD-specific s igns seen at simple . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 17 examination. We found no eligible de finit ions that could be used as a sta rti ng point for o tologic exacerbations. Throughout the process, our panel hi ghlighted the need to selec t elements which could be assessed easil y, in dif feren t set tings and would not requ ire complex ENT examination or a specialis t with expe rtise in PCD to ass ess them. Most cri teria refe r to symp toms, or signs that can be observed in simple c linica l exa mination, the most complex assessment includ ed being otoscopy. Panel members agreed tha t patient s with PCD often unde restim ate thei r upper airway symptoms, which are non-specific and to which they grown accusto med over time, highlighting the need to a lso cons ider simple signs in the de fini tions.[4, 7, 5 5, 56 ] This was also shown in a recent study from the ENT Prospective Int ernati onal Cohort of PCD Patients (EPIC - PCD) that reported a lack o f corr elat i on between sinonasa l and oto logic sy mptoms with

measurements.[57, 58] Two components that requir ed long discussions and voting rounds wer e d octor’s deci sion t o treat and th e need f or improvement of the symptoms and signs. In both d efinit ions, decis ion to treat was inc luded as minor cr iter ion since it could o ccur r egardless of an e xacerbation ( e.g. detecti on of Pseudomonas aeruginos a in a routin e nasal or ear sample). The panel clar ifie d that treatment should n ot on ly ref er to ne ed for ant ibiot ics but a lso oth er medi cation or mana gement practices such as upp er airway clearance. R eturn to basel ine was a term that was not found agreeable t o most panel members. Even though improvement i n symptoms and signs, where foll ow-up examination is possi ble, was included as a minor c rite rion for the sinonasal definit ion, parti cipants agreed that i t is diff icul t to measure improvement a s deteri oration is partly expec ted due to the chroni c na ture of the dis ease. In case of a cute e ar exacerbati ons especiall y, this was not conside red po ssible, and it was no t includ ed at al l i n the defi niti on. This initiat ive was deve loped in the f r amework of the BEAT-P CD ERS clinical research collabora tion ( h ttps://beat-pcd.squar espace.com ), as part of our eff orts to define and pr omote the use of reliab le cl inical outcome measures for PCD trial and cl inical rese arch.[20] Evidence- base for PCD treatment is small, and t here are no trials which have acc esse d specifi cally mana gement of the upper ai rways. Identify ing the most suitabl e cl inical an d patient-repor ted . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 18 outcomes to be used as endpoin ts fo cused on the upp er and lower a irway s, was one of the t op priori ties r elated to PCD research id e ntified recen tly by experts in the field . As more trials are needed to improve care o f PCD and new potential therapi es are i n the pip e line, these definit ions might offe r a usefu l outc o me measure in differen t resea rch set tings. It is important to use and val idate th em in future stu dies and tr ials, to assess thei r usabil it y together with other pot entia l outcomes. . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 19 Funding: The study was supported by a Swiss National Scienc e Foundation Ambizione fellowship (PZ00P3_185 923) granted to M Goutak i. Several auth ors par tici pate in the BEAT- PCD clinica l resear ch col laborati on, co-chaired by M Gou taki and supp orted b y t he European Respirato ry Socie ty, and many centre s participa te in the ERN-LUNG (European Referen ce Network on ra re resp irator y disease s) PCD core. Conflict of interest: No potent ial co nflict of inte rest rele vant t o th is ar ti cle was rep orted. JF Papon reports personal fe es from Sanofi, GSK, Medtronic and ALK outsid e the submitted work. AL Poirrier rec eived spea ker hon orari um from GSK outside the submitted work. Acknowledgments : We would like to thank Jeane tte Bo yd from the Europ e an Lung Foundation (ELF) and the group of peopl e affe cte d by PCD who have supported this p r oject by par ticipa ting in the eDe lphi surveys and providing f eedback outs ide of the con sensus ex pert panel, namely: Tanja Hedberg (S weden), Ta mar Makhatadze (Geo rgia), Nina Peters (UK), Poonam Sodha (U K) and Peter van Baalen (N ether lands). Author Contributions: M Goutaki an d JF Papon developed the concept an d designed the study. YT La m performed the lit eratur e sear ch. M Goutaki managed the study, de signed the eDelph i surveys, analysed the data, and draf t ed the manuscript. All au thors co ntri buted to t he surve ys, interpre ted re sults, and revised c riti c ally the manuscrip t. M Goutak i and JF Papon take final responsibi lity for a ll con tent. Data availability : All data generated f or this p roject was made available in the manuscript display it ems or supplementary infor mation. . CC-BY-NC 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 9, 2024. ; https://doi.org/10.1101/2024.03.08.24303910doi: medRxiv preprint 20

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