The prevalence of bronchiectasis in patients with alpha-1 antitrypsin deficiency: Initial report of EARCO

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Stockley, Anita Pye, Joshua DeSoyza, Alice Turner, Marc Miravitlles This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2612082/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Aug, 2023 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 5 You are reading this latest preprint version Abstract Background Although bronchiectasis has been recognised as a feature of some patients with Alpha1-Antitrypsin deficiency the prevalence and characteristics are not widely known. We wished to determine the prevalence of bronchiectasis and patient characteristics. The first cohort of patients recruited to the EARCO (European Alpha1 Research Collaboration) International Registry data base by the end of 2021 was analysed for radiological evidence of both emphysema and bronchiectasis as well as baseline demographic features. Results Of the first 505 patients with the PiZZ genotype entered into the data base 418 (82.8%) had a reported CT scan. There were 77 (18.4%) with a normal scan and 38 (9.1%) with bronchiectasis alone. These 2 groups were predominantly female never smokers and had lung function in the normal range. The remaining 303 (72.5%) ZZ patients all had emphysema on the scan and 113 (27%) had additional evidence of bronchiectasis. Conclusions The data indicates the bronchiectasis alone is a feature of 9.1% of patients with the PiZZ genotype of Alpha1-antitrypsin deficiency but although emphysema is the dominant lung pathology bronchiectasis is also present in 27% of emphysema cases and may require a different treatment strategy. Alpha-1 antitrypsin deficiency Bronchiectasis Emphysema Prevalence Figures Figure 1 Figure 2 Background Alpha-1 antitrypsin (AAT) is a polyvalent protein with many putative functions ( 1 ) but thought to be primarily an irreversible inhibitor of neutrophil serine proteinases ( 2 ). These enzymes particularly neutrophil elastase (NE) and proteinase 3 (PR3), have been shown to induce emphysematous and airway changes similar to features of chronic obstructive pulmonary disease (COPD) when instilled into the lungs of experimental animals ( 2 ). Initial studies reported by Eriksson ( 3 ) using trypsin inhibitory capacity as the marker of AAT deficiency demonstrated that individuals and family members had clinical features varying from none to severe early onset emphysema and bronchiectasis (Bx). This resulted in widespread testing and reporting of individuals especially those with severe early onset basal panlobular emphysema and sporadic case reports ( 4 ) and analysed cohorts ( 5 – 8 ) of those with Bx. Many patients with COPD have significant bacterial colonisation of the airways and a corresponding neutrophilic load characterised by purulent (elastase positive) secretions ( 9 , 10 ). Radiologically these patients often have Bx ( 10 ) which lead to the concept that the increased neutrophilic load and hence excess local NE release could damage airways, impair host defences and facilitate bacterial colonisation ( 11 ) leading to a self- perpetuating cycle of events ( 12 ). It therefore seems logical that AAT deficiency itself would add another amplifying factor to the pathophysiology of Bx. Indeed in COPD, AAT deficiency is associated with greater airways inflammation (particularly during exacerbations) and detectable active NE even in the stable state ( 13 ); AAT augmentation abrogates this increased inflammation ( 14 ). However, a recent publication has suggested that routine testing of Bx patients for AAT deficiency is not recommended as it is rarely fruitful (< 10%) and does not influence management ( 15 ). This has been questioned ( 16 ) as the prevalence of deficiency in such cohorts is clearly higher than expected in the UK indigenous general population ( 17 ) and indeed may influence current and future management as systemic AAT augmentation abrogates the airways inflammatory process in AATD ( 14 ) and hence excessive putative local airway damage. The recent establishment of EARCO (European Alpha1 Research Collaboration) International Registry, a deep phenotyping data base of AAT deficiency patients sponsored by the European Respiratory Society (ERS) enables us to estimate the prevalence of Bx in AAT deficiency as a baseline to understanding its nature, impact and management. The current article presents the initial findings of patients recruited to EARCO up to December 2021 ( 18 ). Methods Recruitment Patients with AAT deficiency were recruited to the ongoing international multicentre observational study to document the natural history of AATD and the impact of augmentation therapy (EARCO study, IRAS ID: 265728, www.clinicaltrials.gov (ID: NCT04180319)). This clinical research collaboration of the ERS has previously been described in detail by Greulich et al ( 19 ). Briefly patients over the age of 18 gave written informed consent for their clinical data to be collected during routine assessments at secondary care sites in Belgium, Czech Republic, Croatia, Estonia, Italy, The Netherlands, Poland, Portugal, Romania, Spain, Sweden, Switzerland, Turkey and United Kingdom. All subjects with confirmed AAT deficiency, as defined by serum AAT levels of less than 11microM (50mg/dl), and/or proteinase inhibitor genotypes ZZ, SZ and heterozygotes or homozygotes for other rare deficient variants were eligible for inclusion in EARCO. Data included extensive baseline demographics as reported recently ( 19 ). For the current study the data base up to December 2021 was searched for all patients with a PiZZ genotype who had undergone a reported CT densitometry scan. Patients were divided into 4 groups namely those with a reported normal scan, evidence of emphysema alone, those with Bx alone and those with reported emphysema and Bx. Assessment of CT scans Bronchiectatic change (namely tubular, cystic or varicose) and the presence of emphysema were reported together with the distribution as either upper or lower zone dominant or widespread. Baseline CT scan data was used to compare prevalence and type of bronchiectasis seen in PiZZ both with and without CT confirmed emphysema. Statistical analysis Patient data for the 4 radiological groups outlined above were analysed using Mann-Whitney U test for FEV 1 , gas transfer and other quantitative variables. Categorical data were analysed using Chi-squared test and p values < 0.05 were accepted as statistically different. Results Data was collected from of the first 860 individual patients recruited to the EARCO registry up to December 2021, of whom 505 had a confirmed PiZZ genotype and 418 (82.8%) of these had a reported CT scan. The baseline characteristics of the whole cohort of PiZZ subjects and the 418 with a CT scan report is shown in Table 1 . The majority of patients were never or ex-smokers at the time of recruitment with only 1.2% currently smoking at baseline. Normal scans were described for 77 patients (18.4%). Bx alone was reported on CT scan for 38 PiZZ patients (9.1%) and emphysema alone was reported for 190 patients (45.5%) but was also present with Bx for 113 patients (27%). Overall 303 patients had emphysema reported on their CT scan (72.5%) and of these 39.6% were described as lower zone in distribution, 21.8% upper zone and 38.6% widespread. The bronchiectasis was not characterised in 42% of those with Bx alone or when present with emphysema. It was described as tubular when present alone (36.8%) or with emphysema (36.6%) and cystic (13.2% and 13.6%) alone or with emphysema respectively. When not generalised it was reported as distributed mainly in the lower zones, 43.4% when present alone and 54.5% of those with emphysema, consistent with the archetypal distribution of emphysema in AATD. Table 1 Baseline characteristics of PiZZ patients enrolled in EARCO registry Whole cohort Patients with CT scan Total, n 505 418 Age, years: Mean (SD) 55.26 (13.6) 57.95 (12.2) Male, n (%) 270 (53.5%) 218 (52.2%) Smoking, n (%) Current 6 (1.2%) 6 (1.4%) Ex-smoker 290 (57.4%) 249 (59.6%) Never 208 (41.2%) 162 (38.8%) Unknown 1 (0.2%) 1(0.2%) Pack years: Mean (SD) 18.70 (13.75) 18.77 (13.80) Post-bronchodilator FEV 1 %: Mean (SD) 62.56% (29.54) 61.42% (29.14) Kco %: Mean (SD) 67.95% (22.91) 66.37% (22.92) Data is shown for the whole cohort and those with a reported CT scan. Data is summarised as mean and standard deviation in parentheses as indicated. All other data is number and percentage of each cohort. FEV 1 is post bronchodilator where available and gas transfer (Kco) is reported as the transfer coefficient corrected for alveolar ventilation. Of the 87 patients in the PiZZ group who had no CT scan report the demographics were similar to the group as a whole with 59.8% male a mean age of 47.8 years (SD = 16.0). Most (52.9%) were never smokers and 47.1% ex-smokers with a mean pack year history of 16.0 (SD = 16.5). Of these 87 patients the average FEV 1 was 88.3% (SD 31.2). Kco was available for 54 of the 87 patients with a mean value of 76.7% predicted (SD 20.9). The baseline characteristics of those with CT scan reports were similar to the total PiZZ cohort (Table 1 ). The four groups of PiZZ subjects defined by the CT findings are summarised in Table 2 . There were some demographic differences between the 4 groups. Those with a normal scan were predominantly female, mainly never smokers and younger with generally near normal lung function compared to the groups with emphysema (p < 0.001). The demographics for this “normal” group was similar to the group of patients who had Bx alone (Table 2 ). The patients with emphysema were older on average (p < 0.001) with a slight male preponderance (p = 0.09), consisted of fewer never smokers and had a greater smoking history compared to those with a normal scan or Bx alone (p < 0.001). In addition, these 2 emphysema groups (with and without Bx) had moderate airflow obstruction and significantly Table 2 Baseline characteristics of 418 PiZZ patients split according to CT scan findings Bronchiectasis alone Emphysema alone Bronchiectasis plus Emphysema Normal CT scan Total, n 38 190 113 77 Age, years: Mean (SD) 57.2 (10.2) 58.8 (9.9) 61.1 (11.0) 46.2 (14.0) Male, n (%) 11 (28.9%) 112 (58.9%) 59 (52.2%) 36 (46.8%) Smoking, n (%) Current 0 4 (2.1%) 0 2 (2.6%) Ex-smoker 12 (31.6%) 140 (73.7%) 77 (68.1%) 20 (26.0%) Never 26 (68.4%) 46 (24.2%) 36 (31.9%) 54 (70.1%) Unknown 0 0 0 1 (1.3%) Pack years: Mean (SD) 14.0 (15.7) 20.8 (13.6) 17.1 (10.1) 9.35 (8.8) Mean FEV 1 % Post BD (SD) 98.3% (18.0) 56.2% (24.3) 59.6% (27.5) 92.6% (20.2) Mean Kco % (SD) 83.1% (17.8) 54.7% (18.9) 65.1% (19.1) 90% (16.9) reduced gas transfer as expected (p < 0.001 compared to those with normal scans or Bx alone). The patients with emphysema and Bx were more likely to be male (p = 0.021), smokers (p < 0.001) and with reduced lung function compared to those with Bx alone (p < 0.001 all measures). The average lung function data corrected for age sex and height for the 4 groups is summarised in Figs. 1 and 2 . Discussion The baseline data from this initial analysis of the first 860 patients uploaded to the EARCO data base identified 505 PiZZ patients of whom 418 had undergone CT scanning as part of their disease characterisation and of these 38 had evidence of Bx alone which is similar to the prevalence found by Eriksson ( 3 ) in his initial 23 patient cohort analysis. Interestingly the small sub cohort reported here was predominantly female and with little smoking history (which may partly explain the lack of emphysema) and predominantly normal lung function. This sex and smoking difference is reminiscent of historical studies where smoking men with the same symptoms but airflow obstruction were often assumed to have COPD and investigated no further, whereas non-smoking females underwent more extensive investigations including radiographic bronchograms. It was often mooted that this reflected a selection bias dependant on investigation whereas here that bias seems unlikely. Clearly Bx alone is a feature of a proportion of patients with PiZZ AATD and is similar to the prevalence described by Carreto et al in specialist Bx clinics ( 15 ) which suggests that continued testing in Bx for this associated genetic defect should still be continued. Whether this leads to different management to non-deficient Bx patients requires much more individual characterisation including bacterial colonisation, airways neutrophilia (and serine proteinase activity), as well as exacerbation history. Whereas this is important in all patients with exacerbations the presence of AATD will likely have an increased inflammatory load ( 12 ) amenable (at least in part) to AAT augmentation intravenously ( 13 ), by the inhaled route ( 20 ) or with more recent oral antiproteinase strategies in development ( 21 ). However with the advent of CT scanning as a non-invasive GOLD standard more cases of Bx are being identified with up to 30% of COPD patients having both emphysema and Bx ( 22 ) suggesting it is a significant comorbidity especially in severity subgroups ( 23 ). In the current study 113 (27%) of PiZZ patients had Bx associated with emphysema which is also similar to the prevalence of easily visible changes described by Parr et al in a smaller but highly characterised cohort ( 15 ), although the prevalence of minor changes that fulfilled the Naidich criteria for Bx ( 24 ) was almost universal. In non-deficient COPD this association influences both mortality ( 25 ) and recurrent exacerbations ( 26 ). Indeed early studies of COPD patients with productive purulent sputum suggesting significant bacterial colonisation ( 9 ) is associated with a high prevalence of Bx ( 10 ). On this basis it has been suggested that such COPD patients with Bx should be considered for additional treatment strategies as for patients with Bx alone ( 22 ) Whether these features are also true of a significant proportion of AATD patients remains to be determined but it is tempting to speculate that (as in COPD) such patients have increased inflammation and may benefit from antiproteinase therapy and specifically Cathepsin C inhibitors ( 27 ) that may reduce both the inflammation and proteinase load in Bx but also influence the proteinase dependant emphysema in AATD patients. The increasing recognition of the associations of Bx with COPD has raised the concept that this represents a treatable trait and the arguments above provide a strategy in both non deficient and AAT deficient patients. More recently a workshop has described the ROSE criteria ( 28 ) for the key components to determine the implications of the combination and its verification. As this recent work was not published when EARCO was established the essential components of the ROSE score were not mandatory in the data base and much of the features of ROSE have not been systematically collected to date. Also, COPD related to AATD (although highly susceptible to smoking which is a key component of the ROSE score) can also develop in never smokers and hence a “ROSE score” may require further adjustment for this component. Clearly this association and score needs further exploration in AATD as well as non-deficient COPD as mentioned by the authors ( 28 ). The current study has the strengths of being an in depth characterisation of AAT deficient patients across many specialist groups and countries and is therefore reflective of the current patient population. It emphasises that many patients do not fulfil the archetypical AATD patient with basal panlobular emphysema, supporting widespread AAT testing in all patients with COPD and those who present with Bx alone. However it does have some weaknesses. In particular, not all patients had CT scans at baseline (although those who did not had similar baseline characteristics of those who did). In addition data on airway colonisation, and nature and frequency of exacerbations are not mandatory fields on the EARCO data base, leading to missing data. The nature and distribution of emphysema as well as characteristics of the Bx are requested within EARCO, but again not mandatory, and should also be described to strict criteria as part of subsequent retrospective and prospective analyses to complete understanding of this combination phenotype and its management. Finally, tests to confirm that other causes of Bx had been excluded were rarely formally reported in the EARCO database, although sites confirmed that it was routine practice to screen for immunodeficiency, take a detailed history of past infections and consider autoimmune or other familial causes. Conclusions In conclusion AAT deficiency is associated with Bx alone in up to 10% of PiZZ individuals and 27% of those with emphysema. This should become a routine part of patients’ assessment and become a feature of in depth future clinical study and management. Abbreviations AAT Alpha-1 antitrypsin NE Neutrophil elastase PR3 Proteinase 3 COPD Chronic obstructive pulmonary disease Bx Bronchiectasis AATD Alpha-1 antitrypsin deficiency EARCO European Alpha1 Research Collaboration) International Registry ERS European Respiratory Society Declarations Ethics approval and consent to participate EARCO received ethics approval in individual countries and all participants gave written informed consent for their data to be included in the EARCO database. In UK the study was approved by London-Camden and Kings Cross Research Ethics Committee, REC Ref: 19/LO/1106. Consent for publication Not applicable Availability of data and materials The datasets generated and/or analysed during the current study are not publicly available due to individual patient privacy and lack of consent but are available from the corresponding author on reasonable request. Competing interests Marc Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Kamada, Takeda, Zambon, CSL Behring, Specialty Therapeutics, Janssen, Grifols and Novartis, consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, CSL Behring, Inhibrx, Ferrer, Menarini, Mereo Biopharma, Spin Therapeutics, ONO Pharma, Palobiofarma SL, Takeda, Novartis, Novo Nordisk, Sanofi, Zambon and Grifols and research grants from Grifols. Alice M Turner has received either grants or speaker fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Chiesi, CSL Behring, Takeda, Vertex and Grifols Biotherapeutics. Robert A Stockley has received research grants from Mereo BioPharma and CSL Behring, consulting fees from Mereo BioPharma, CSL Behring, Vertex, Inhibrx and chairs the DSMB for Takeda. Funding The International EARCO registry is funded by unrestricted grants of Grifols, CSL Behring, Kamada, pH Pharma and Takeda to the European Respiratory Society (ERS). Authors’ contributions RS proposed the study and was the major author interpreting the data, writing and preparing the manuscript for publication. AP analysed the patient data and contributed to the preparation of the manuscript. JD performed statistical analysis on the patient data. AT is the UK lead for EARCO, contributed to data interpretation and revised the manuscript. MM is the chair of EARCO, contributed to data interpretation and revised the manuscript. All authors reviewed and approved the final manuscript. Acknowledgements The authors would like to thank the patients who participated in this study and the EARCO study investigators (listed below) all of whom contributed >10 patients to the EARCO data base. We wish to acknowledge Elise Heuvelin from the ERS office (Lausanne, Switzerland) for her support in the management of EARCO, and Gemma Vilagut and Christina Founti (Bioclever, Barcelona, Spain) for their support in EARCO data monitoring. List of EARCO study investigators: Georg-Christian Funk (Austria), Wim Janssens, Silvia Pérez-Bogerd (Belgium), Leidy Prada (Colombia), Ana Hecimovic (Croatia), Eva Bartosovska, Jan Chlumsky, (Czech Republic), Alan Altraja, Jaanus Martti (Estonia), Angelo G. Corsico, Ilaria Ferrarotti, Simone Scarlata, Mario Malerba (Italy), Jan Stolk, Emily F van’t Wout (Netherlands), Joanna Chorowstoska-Wyminko (Poland), Catarina Guimaraes, Maria Sucena, Ana Caldas Raquel Marçoa, Isabel Ruivo dos Santos, Bebiana Conde, Maria Joana Reis Amado Maia Da Silva, Rita Boaventura (Portugal), Ruxandra Ulmeanu (Romania), María Torres-Duran, Marc Miravitlles, Miriam Barrecheguren, Juan Luis Rodriguez-Hermosa, Myriam Calle-Rubio, José María Hernández-Pérez, José Luis López-Campos, Francisco Casas-Maldonado, Ana Bustamante, Carlota Rodriguez-García, Cristina Martinez-González, Cruz González, Eva Tabernero, Lourdes Lázaro, Virginia Almadana, Mar Fernández-Nieto, Francisco Javier Michel de la Rosa, Carlos Martíez-Rivera, Layla Diab, María Isabel Parra (Spain), Hanan Tanash, Eeva Piitulainen (Sweden), Christian F Clarenbach (Switzerland), Serap Argun Baris, Dilek Karadogan, Sebahat Genç (Turkey), Alice M Turner, Beatriz Lara, David G Parr (United Kingdom). 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Cite Share Download PDF Status: Published Journal Publication published 12 Aug, 2023 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Minor revision 30 May, 2023 Reviewers invited by journal 15 Apr, 2023 Reviewers agreed at journal 04 Mar, 2023 Editor assigned by journal 01 Mar, 2023 First submitted to journal 27 Feb, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2612082","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":180738334,"identity":"5684f9ec-8ec7-478d-b65f-96796d7ae8e3","order_by":0,"name":"Robert A. Stockley","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIie3PMUsDMRTA8ReepEug65MU+xVaCpXC+V2eCJnOLoXiKByki7crfpmTgC6S2cGli3MmOTdzXsHprnUTmv/wAnf5wQtAKvUvU+1BgzgCVLz7wntI/E8IIO7/TFAdQs43ZSW+6mx8WuCzvrDvS9ClC8KaTjJ69YyKzfQRpdHX9mMFI29I2LyTEOUTBHZ8hmoeibu8pXwOwt70ElH/kOGnXrRkFvYRUJFoVFKLlkz6F1OenTJm+lDI2eLOu5WMixH77ufToHza1lk2ppdi+1av3XLYLBbWV52kqdqdJ9RM2QzuBb9hOPBiKpVKHVnfr7tLwF73l+cAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-3726-1207","institution":"Queen Elizabeth Hospital Birmingham","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Robert","middleName":"A.","lastName":"Stockley","suffix":""},{"id":180738335,"identity":"a6573afb-cdff-4791-99a8-b2f91c317bbe","order_by":1,"name":"Anita Pye","email":"","orcid":"","institution":"University of Birmingham Institute of Biomedical Research: University of Birmingham College of Medical and Dental Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anita","middleName":"","lastName":"Pye","suffix":""},{"id":180738336,"identity":"2490c844-a7f9-4021-b2cf-621420ab26c5","order_by":2,"name":"Joshua DeSoyza","email":"","orcid":"","institution":"University of Birmingham Institute of Biomedical Research: University of Birmingham College of Medical and Dental Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Joshua","middleName":"","lastName":"DeSoyza","suffix":""},{"id":180738337,"identity":"aef6f730-c361-4ff6-8cf3-f7d086576797","order_by":3,"name":"Alice Turner","email":"","orcid":"","institution":"University of Birmingham Institute of Biomedical Research: University of Birmingham College of Medical and Dental Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alice","middleName":"","lastName":"Turner","suffix":""},{"id":180738338,"identity":"f2a36b1d-b9ac-4c15-b2ff-583cd9059627","order_by":4,"name":"Marc Miravitlles","email":"","orcid":"","institution":"Vall d'Hebron Hospital Universitari","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marc","middleName":"","lastName":"Miravitlles","suffix":""}],"badges":[],"createdAt":"2023-02-21 12:27:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2612082/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2612082/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-023-02830-2","type":"published","date":"2023-08-12T21:55:40+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":34041245,"identity":"dcebdba9-2760-4e30-8cd5-aca0ab3ab104","added_by":"auto","created_at":"2023-03-09 23:58:02","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":160498,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePost-bronchodilator FEV\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e % predicted in patients with PiZZ alpha-1 antitrypsin deficiency according to CT pathology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHistograms are mean data for ex-smokers and never smokers with SD bars. p values indicate differences compared to emphysema alone and the combined group.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2612082/v1/3592891051970cae46aa3f7f.jpeg"},{"id":34041246,"identity":"3b8ddcc2-27c3-4952-adc4-ab0474fe6de3","added_by":"auto","created_at":"2023-03-09 23:58:02","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":157298,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKco % predicted in patients with PiZZ alpha-1 antitrypsin deficiency according to CT pathology.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHistograms are the mean with SD bars for ex-smokers and never smokers p values indicate differences compared to emphysema alone and the combined group.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-2612082/v1/7071440d3917b985a90e2ecc.jpeg"},{"id":44734983,"identity":"08a554da-bca4-4f78-884c-e735ee154dbf","added_by":"auto","created_at":"2023-10-16 22:22:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":404001,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2612082/v1/1c0581b4-b93c-47a8-8eb8-0995ce4bf187.pdf"}],"financialInterests":"","formattedTitle":"The prevalence of bronchiectasis in patients with alpha-1 antitrypsin deficiency: Initial report of EARCO","fulltext":[{"header":"Background","content":"\u003cp\u003eAlpha-1 antitrypsin (AAT) is a polyvalent protein with many putative functions (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) but thought to be primarily an irreversible inhibitor of neutrophil serine proteinases (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). These enzymes particularly neutrophil elastase (NE) and proteinase 3 (PR3), have been shown to induce emphysematous and airway changes similar to features of chronic obstructive pulmonary disease (COPD) when instilled into the lungs of experimental animals (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInitial studies reported by Eriksson (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) using trypsin inhibitory capacity as the marker of AAT deficiency demonstrated that individuals and family members had clinical features varying from none to severe early onset emphysema and bronchiectasis (Bx). This resulted in widespread testing and reporting of individuals especially those with severe early onset basal panlobular emphysema and sporadic case reports (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) and analysed cohorts (\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) of those with Bx.\u003c/p\u003e \u003cp\u003eMany patients with COPD have significant bacterial colonisation of the airways and a corresponding neutrophilic load characterised by purulent (elastase positive) secretions (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Radiologically these patients often have Bx (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) which lead to the concept that the increased neutrophilic load and hence excess local NE release could damage airways, impair host defences and facilitate bacterial colonisation (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) leading to a self- perpetuating cycle of events (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). It therefore seems logical that AAT deficiency itself would add another amplifying factor to the pathophysiology of Bx. Indeed in COPD, AAT deficiency is associated with greater airways inflammation (particularly during exacerbations) and detectable active NE even in the stable state (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e); AAT augmentation abrogates this increased inflammation (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, a recent publication has suggested that routine testing of Bx patients for AAT deficiency is not recommended as it is rarely fruitful (\u0026lt;\u0026thinsp;10%) and does not influence management (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). This has been questioned (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) as the prevalence of deficiency in such cohorts is clearly higher than expected in the UK indigenous general population (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) and indeed may influence current and future management as systemic AAT augmentation abrogates the airways inflammatory process in AATD (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) and hence excessive putative local airway damage.\u003c/p\u003e \u003cp\u003eThe recent establishment of EARCO (European Alpha1 Research Collaboration) International Registry, a deep phenotyping data base of AAT deficiency patients sponsored by the European Respiratory Society (ERS) enables us to estimate the prevalence of Bx in AAT deficiency as a baseline to understanding its nature, impact and management. The current article presents the initial findings of patients recruited to EARCO up to December 2021 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment\u003c/h2\u003e \u003cp\u003ePatients with AAT deficiency were recruited to the ongoing international multicentre observational study to document the natural history of AATD and the impact of augmentation therapy (EARCO study, IRAS ID: 265728, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.clinicaltrials.gov\" target=\"_blank\"\u003ewww.clinicaltrials.gov\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.clinicaltrials.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (ID: NCT04180319)). This clinical research collaboration of the ERS has previously been described in detail by Greulich \u003cem\u003eet al\u003c/em\u003e (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBriefly patients over the age of 18 gave written informed consent for their clinical data to be collected during routine assessments at secondary care sites in Belgium, Czech Republic, Croatia, Estonia, Italy, The Netherlands, Poland, Portugal, Romania, Spain, Sweden, Switzerland, Turkey and United Kingdom. All subjects with confirmed AAT deficiency, as defined by serum AAT levels of less than 11microM (50mg/dl), and/or proteinase inhibitor genotypes ZZ, SZ and heterozygotes or homozygotes for other rare deficient variants were eligible for inclusion in EARCO. Data included extensive baseline demographics as reported recently (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). For the current study the data base up to December 2021 was searched for all patients with a PiZZ genotype who had undergone a reported CT densitometry scan. Patients were divided into 4 groups namely those with a reported normal scan, evidence of emphysema alone, those with Bx alone and those with reported emphysema and Bx.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAssessment of CT scans\u003c/h2\u003e \u003cp\u003eBronchiectatic change (namely tubular, cystic or varicose) and the presence of emphysema were reported together with the distribution as either upper or lower zone dominant or widespread. Baseline CT scan data was used to compare prevalence and type of bronchiectasis seen in PiZZ both with and without CT confirmed emphysema.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003ePatient data for the 4 radiological groups outlined above were analysed using Mann-Whitney U test for FEV\u003csub\u003e1\u003c/sub\u003e, gas transfer and other quantitative variables. Categorical data were analysed using Chi-squared test and p values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were accepted as statistically different.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eData was collected from of the first 860 individual patients recruited to the EARCO registry up to December 2021, of whom 505 had a confirmed PiZZ genotype and 418 (82.8%) of these had a reported CT scan. The baseline characteristics of the whole cohort of PiZZ subjects and the 418 with a CT scan report is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The majority of patients were never or ex-smokers at the time of recruitment with only 1.2% currently smoking at baseline. Normal scans were described for 77 patients (18.4%). Bx alone was reported on CT scan for 38 PiZZ patients (9.1%) and emphysema alone was reported for 190 patients (45.5%) but was also present with Bx for 113 patients (27%). Overall 303 patients had emphysema reported on their CT scan (72.5%) and of these 39.6% were described as lower zone in distribution, 21.8% upper zone and 38.6% widespread. The bronchiectasis was not characterised in 42% of those with Bx alone or when present with emphysema. It was described as tubular when present alone (36.8%) or with emphysema (36.6%) and cystic (13.2% and 13.6%) alone or with emphysema respectively. When not generalised it was reported as distributed mainly in the lower zones, 43.4% when present alone and 54.5% of those with emphysema, consistent with the archetypal distribution of emphysema in AATD.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of PiZZ patients enrolled in EARCO registry\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWhole cohort\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients with CT scan\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e505\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e418\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years: Mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.26 (13.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.95 (12.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e270 (53.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e218 (52.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (1.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (1.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEx-smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e290 (57.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e249 (59.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e208 (41.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e162 (38.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(0.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePack years: Mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.70 (13.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.77 (13.80)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost-bronchodilator FEV\u003csub\u003e1\u003c/sub\u003e%: Mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.56% (29.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.42% (29.14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKco %: Mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.95% (22.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.37% (22.92)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eData is shown for the whole cohort and those with a reported CT scan. Data is summarised as mean and standard deviation in parentheses as indicated. All other data is number and percentage of each cohort. FEV\u003c/em\u003e \u003csub\u003e \u003cem\u003e1\u003c/em\u003e \u003c/sub\u003e \u003cem\u003eis post bronchodilator where available and gas transfer (Kco) is reported as the transfer coefficient corrected for alveolar ventilation.\u003c/em\u003e\u003c/p\u003e \u003cp\u003eOf the 87 patients in the PiZZ group who had no CT scan report the demographics were similar to the group as a whole with 59.8% male a mean age of 47.8 years (SD\u0026thinsp;=\u0026thinsp;16.0). Most (52.9%) were never smokers and 47.1% ex-smokers with a mean pack year history of 16.0 (SD\u0026thinsp;=\u0026thinsp;16.5). Of these 87 patients the average FEV\u003csub\u003e1\u003c/sub\u003e was 88.3% (SD 31.2). Kco was available for 54 of the 87 patients with a mean value of 76.7% predicted (SD 20.9). The baseline characteristics of those with CT scan reports were similar to the total PiZZ cohort (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe four groups of PiZZ subjects defined by the CT findings are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. There were some demographic differences between the 4 groups. Those with a normal scan were predominantly female, mainly never smokers and younger with generally near normal lung function compared to the groups with emphysema (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The demographics for this \u0026ldquo;normal\u0026rdquo; group was similar to the group of patients who had Bx alone (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The patients with emphysema were older on average (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) with a slight male preponderance (p\u0026thinsp;=\u0026thinsp;0.09), consisted of fewer never smokers and had a greater smoking history compared to those with a normal scan or Bx alone (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In addition, these 2 emphysema groups (with and without Bx) had moderate airflow obstruction and significantly\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of 418 PiZZ patients split according to CT scan findings\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBronchiectasis alone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEmphysema alone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBronchiectasis plus Emphysema\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNormal CT scan\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e190\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years: Mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57.2 (10.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.8 (9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61.1 (11.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e46.2 (14.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (28.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e112 (58.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59 (52.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36 (46.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (2.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (2.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEx-smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (31.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e140 (73.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77 (68.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 (26.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (68.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (24.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (31.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e54 (70.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePack years: Mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.0 (15.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.8 (13.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.1 (10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.35 (8.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean FEV\u003csub\u003e1\u003c/sub\u003e%\u003c/p\u003e \u003cp\u003ePost BD (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98.3% (18.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56.2% (24.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59.6% (27.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e92.6% (20.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean Kco % (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83.1% (17.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54.7% (18.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.1% (19.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90% (16.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ereduced gas transfer as expected (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 compared to those with normal scans or Bx alone). The patients with emphysema and Bx were more likely to be male (p\u0026thinsp;=\u0026thinsp;0.021), smokers (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and with reduced lung function compared to those with Bx alone (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 all measures). The average lung function data corrected for age sex and height for the 4 groups is summarised in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe baseline data from this initial analysis of the first 860 patients uploaded to the EARCO data base identified 505 PiZZ patients of whom 418 had undergone CT scanning as part of their disease characterisation and of these 38 had evidence of Bx alone which is similar to the prevalence found by Eriksson (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) in his initial 23 patient cohort analysis. Interestingly the small sub cohort reported here was predominantly female and with little smoking history (which may partly explain the lack of emphysema) and predominantly normal lung function. This sex and smoking difference is reminiscent of historical studies where smoking men with the same symptoms but airflow obstruction were often assumed to have COPD and investigated no further, whereas non-smoking females underwent more extensive investigations including radiographic bronchograms. It was often mooted that this reflected a selection bias dependant on investigation whereas here that bias seems unlikely.\u003c/p\u003e \u003cp\u003eClearly Bx alone is a feature of a proportion of patients with PiZZ AATD and is similar to the prevalence described by Carreto \u003cem\u003eet al\u003c/em\u003e in specialist Bx clinics (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) which suggests that continued testing in Bx for this associated genetic defect should still be continued. Whether this leads to different management to non-deficient Bx patients requires much more individual characterisation including bacterial colonisation, airways neutrophilia (and serine proteinase activity), as well as exacerbation history. Whereas this is important in all patients with exacerbations the presence of AATD will likely have an increased inflammatory load (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) amenable (at least in part) to AAT augmentation intravenously (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), by the inhaled route (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) or with more recent oral antiproteinase strategies in development (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever with the advent of CT scanning as a non-invasive GOLD standard more cases of Bx are being identified with up to 30% of COPD patients having both emphysema and Bx (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) suggesting it is a significant comorbidity especially in severity subgroups (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). In the current study 113 (27%) of PiZZ patients had Bx associated with emphysema which is also similar to the prevalence of easily visible changes described by Parr \u003cem\u003eet al\u003c/em\u003e in a smaller but highly characterised cohort (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), although the prevalence of minor changes that fulfilled the Naidich criteria for Bx (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) was almost universal. In non-deficient COPD this association influences both mortality (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) and recurrent exacerbations (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Indeed early studies of COPD patients with productive purulent sputum suggesting significant bacterial colonisation (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) is associated with a high prevalence of Bx (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). On this basis it has been suggested that such COPD patients with Bx should be considered for additional treatment strategies as for patients with Bx alone (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) Whether these features are also true of a significant proportion of AATD patients remains to be determined but it is tempting to speculate that (as in COPD) such patients have increased inflammation and may benefit from antiproteinase therapy and specifically Cathepsin C inhibitors (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) that may reduce both the inflammation and proteinase load in Bx but also influence the proteinase dependant emphysema in AATD patients.\u003c/p\u003e \u003cp\u003eThe increasing recognition of the associations of Bx with COPD has raised the concept that this represents a treatable trait and the arguments above provide a strategy in both non deficient and AAT deficient patients. More recently a workshop has described the ROSE criteria (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) for the key components to determine the implications of the combination and its verification. As this recent work was not published when EARCO was established the essential components of the ROSE score were not mandatory in the data base and much of the features of ROSE have not been systematically collected to date. Also, COPD related to AATD (although highly susceptible to smoking which is a key component of the ROSE score) can also develop in never smokers and hence a \u0026ldquo;ROSE score\u0026rdquo; may require further adjustment for this component. Clearly this association and score needs further exploration in AATD as well as non-deficient COPD as mentioned by the authors (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe current study has the strengths of being an in depth characterisation of AAT deficient patients across many specialist groups and countries and is therefore reflective of the current patient population. It emphasises that many patients do not fulfil the archetypical AATD patient with basal panlobular emphysema, supporting widespread AAT testing in all patients with COPD and those who present with Bx alone. However it does have some weaknesses. In particular, not all patients had CT scans at baseline (although those who did not had similar baseline characteristics of those who did). In addition data on airway colonisation, and nature and frequency of exacerbations are not mandatory fields on the EARCO data base, leading to missing data. The nature and distribution of emphysema as well as characteristics of the Bx are requested within EARCO, but again not mandatory, and should also be described to strict criteria as part of subsequent retrospective and prospective analyses to complete understanding of this combination phenotype and its management. Finally, tests to confirm that other causes of Bx had been excluded were rarely formally reported in the EARCO database, although sites confirmed that it was routine practice to screen for immunodeficiency, take a detailed history of past infections and consider autoimmune or other familial causes.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion AAT deficiency is associated with Bx alone in up to 10% of PiZZ individuals and 27% of those with emphysema. This should become a routine part of patients\u0026rsquo; assessment and become a feature of in depth future clinical study and management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAAT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Alpha-1 antitrypsin\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Neutrophil elastase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePR3\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Proteinase 3\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCOPD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Chronic obstructive pulmonary disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBx\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Bronchiectasis\u003c/p\u003e\n\u003cp\u003eAATD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Alpha-1 antitrypsin deficiency\u003c/p\u003e\n\u003cp\u003eEARCO\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;European Alpha1 Research Collaboration) International Registry\u003c/p\u003e\n\u003cp\u003eERS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;European Respiratory Society\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEARCO received ethics approval in individual countries and all participants gave written informed consent for their data to be included in the EARCO database.\u003c/p\u003e\n\u003cp\u003eIn UK the study was approved by London-Camden and Kings Cross Research Ethics Committee, REC Ref: 19/LO/1106.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due to individual patient privacy and lack of consent but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMarc Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Kamada, Takeda, Zambon, CSL Behring, Specialty Therapeutics, Janssen, Grifols and Novartis, consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, CSL Behring, Inhibrx, Ferrer, Menarini, Mereo Biopharma, Spin Therapeutics, ONO Pharma, Palobiofarma SL, Takeda, Novartis, Novo Nordisk, Sanofi, Zambon and Grifols and research grants from Grifols. Alice M Turner has received either grants or speaker fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Chiesi, CSL Behring, Takeda, Vertex and Grifols Biotherapeutics. Robert A Stockley has received research grants from Mereo BioPharma and CSL Behring, consulting fees from Mereo BioPharma, CSL Behring, Vertex, Inhibrx and chairs the DSMB for Takeda.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe International EARCO registry is funded by unrestricted grants of Grifols, CSL Behring, Kamada, pH Pharma and Takeda to the European Respiratory Society (ERS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRS proposed the study and was the major author interpreting the data, writing and preparing the manuscript for publication. AP analysed the patient data and contributed to the preparation of the manuscript. JD performed statistical analysis on the patient data. AT is the UK lead for EARCO, contributed to data interpretation and revised the manuscript. MM is the chair of EARCO, contributed to data interpretation and revised the manuscript. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the patients who participated in this study and the EARCO study investigators (listed below) all of whom contributed \u0026gt;10 patients to the EARCO data base. We wish to acknowledge Elise Heuvelin from the ERS office (Lausanne, Switzerland) for her support in the management of EARCO, and Gemma Vilagut and Christina Founti (Bioclever, Barcelona, Spain) for their support in EARCO data monitoring.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eList of EARCO study investigators: Georg-Christian Funk (Austria), Wim Janssens, Silvia P\u0026eacute;rez-Bogerd (Belgium), Leidy Prada (Colombia), Ana Hecimovic (Croatia), Eva Bartosovska, Jan Chlumsky, (Czech Republic), Alan Altraja, Jaanus Martti (Estonia), Angelo G. Corsico, Ilaria Ferrarotti, Simone Scarlata, Mario Malerba (Italy), Jan Stolk, Emily F van\u0026rsquo;t Wout (Netherlands), Joanna Chorowstoska-Wyminko (Poland), Catarina Guimaraes, Maria Sucena, Ana Caldas Raquel Mar\u0026ccedil;oa, Isabel Ruivo dos Santos, Bebiana Conde, Maria Joana Reis Amado Maia Da Silva, Rita Boaventura (Portugal), Ruxandra Ulmeanu (Romania), Mar\u0026iacute;a Torres-Duran, Marc Miravitlles, Miriam Barrecheguren, Juan Luis Rodriguez-Hermosa, Myriam Calle-Rubio, Jos\u0026eacute; Mar\u0026iacute;a Hern\u0026aacute;ndez-P\u0026eacute;rez, Jos\u0026eacute; Luis L\u0026oacute;pez-Campos, Francisco Casas-Maldonado, Ana Bustamante, Carlota Rodriguez-Garc\u0026iacute;a, Cristina Martinez-Gonz\u0026aacute;lez, Cruz Gonz\u0026aacute;lez, Eva Tabernero, Lourdes L\u0026aacute;zaro, Virginia Almadana, Mar Fern\u0026aacute;ndez-Nieto, Francisco Javier Michel de la Rosa, Carlos Mart\u0026iacute;ez-Rivera, Layla Diab, Mar\u0026iacute;a Isabel Parra \u0026nbsp;(Spain), Hanan Tanash, Eeva Piitulainen (Sweden), Christian F Clarenbach (Switzerland), Serap Argun Baris, Dilek Karadogan, Sebahat Gen\u0026ccedil; (Turkey), Alice M Turner, Beatriz Lara, David G Parr (United Kingdom). EARCO Steering committee: Christian F Clarenbach and Marc Miravitlles (Co-chairs), Robert Bals, Jan Stolk, Joanna Chorostowska-Wynimko, Karen O\u0026rsquo;Hara, Marion Wilkens, Jos\u0026eacute; Luis L\u0026oacute;pez-Campos, Alice M. Turner, Ilaria Ferrarotti, Gerry McElvaney and Robert A. Stockley.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStockley RA. α1-antitrypsin: a polyfunctional protein? Lancet Resp Med. 2015;3(5):341\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCrisford H, Sapey E, Stockley RA. Proteinase 3; a potential target in chronic obstructive pulmonary disease and other chronic inflammatory disease. Respir Res. 2018;19:180.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEriksson S. Pulmonary emphysema and alpha-1 antitrypsin deficiency. Acta Med Scand. 1964;175:197\u0026ndash;205.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuest PJ, Hansell DM. 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Chronic Obstr Pulm Dis. 2019;6:145\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCuvelier A, Muir JF, Hellot MF, Benhamou D, Martin JP, Benichou J, Sesboue R. Distribution of alpha(1)-antitrypsin alleles in patients with bronchiectasis. Chest. 2000;117:415\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLonni S, Chalmers JD, Goeminne PC, McDonnell MJ, Dimakou K, De Soyza A, Polverino E, Van de kerkhove C, Rutherford R, Davison J, Rosales E, Pesci A, Restrepo MI, Torres A, Aliberti S. Etiology of Non\u0026ndash;Cystic Fibrosis Bronchiectasis in Adults and Its Correlation to Disease Severity. Ann Am Thorac Soc. 2015;12(12):1764\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHill AT, Campbell EJ, Hill SL, Bayley D, Stockley RA. Association between airway bacterial load and markers of inflammation in patients with stable chronic bronchitis. Am J Med. 2000;109:288\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCooke JC, Currie DC, Morgan AD, Kerr IH, Delany D, Strickland B, Cole PJ. Role of computed tomography in diagnosis of bronchiectasis. Thorax. Apr; 1987;42(4):272\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhitters D, Stockley RA. Immunity and bacterial colonization in bronchiectasis. Thorax. 2012;67:1006\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStockley RA, Bronchiectasis. 1999 Medicine, 27; 10: 113\u0026ndash;116\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHill AT, Bayley DL, Campbell EJ, Hill SL, Stockley RA. Airways inflammation in chronic bronchitis: the effects of smoking and α1-antitrypsin deficiency. Eur Respir J. 2000;15:886\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStockley RA, Bayley DL, Unsal I, Dowson L. The effect of augmentation therapy on bronchial inflammation in α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2002;165:1494\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarreto L, Morrison M, Donovan J, Finch S, Tan GL, Fardon T, Wilson R, Furrie E, Loebinger M, Chalmers JD. Utility of routine screening for alpha-1 antitrypsin deficiency in patients with bronchiectasis. Thorax. 2020 Jul;75(7):592\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1136/thoraxjnl-2019-214195\u003c/span\u003e\u003cspan address=\"10.1136/thoraxjnl-2019-214195\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Rapid response.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Serres FJ, Blanco I. Prevalence of α1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review. Ther Adv Respir Dis. 2012 Oct;6(5):277\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiravitlles M, Turner AM, Torres-Duran M, Tanash H, Rodr\u0026iacute;guez-Garc\u0026iacute;a C, L\u0026oacute;pez-Campos JL, Chlumsky J, Guimaraes C, Rodr\u0026iacute;guez-Hermosa JL, Corsico A, Martinez-Gonz\u0026aacute;lez C, Hern\u0026aacute;ndez-P\u0026eacute;rez JM, Bustamante A, Parr DG, Casas-Maldonado F, Hecimovic A, Janssens W, Lara B, Barrecheguren M, Gonz\u0026aacute;lez C, Stolk J, Esquinas C, Clarenbach CF. Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry. Respir Res. 2022 Dec;16(1):352.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreulich T, Altraja A, Barrecheguren M, Bals R, Chlumsky J, Chorostowska-Wynimko J, Clarenbach C, Corda L, Corsico AG, Ferrarotti I, Esquinas C, Gouder C, Hećimović A, Ilic A, Ivanov Y, Janciauskiene S, Janssens W, Kohle MR, Krams A, Lara B, Mahadeva R, McElvaney G, Mornex J-F, O'Hara K, Parr D, Piitulainen E, Schmid-Scherzer K, Seersholm N, Stockley RA, Stolk J, Sucena M, Tanash H, Turner A, Ulmeanu R, Wilkens M, Yorgancioğlu A, Zaharie A, Miravitlles M, on behalf of the EARCO Clinical Research Collaboration. Protocol for the EARCO Registry: a pan-European observational study in patients with α\u003csub\u003e1\u003c/sub\u003e-antitrypsin deficiency. ERJ Open Res. 2020 Jan;6(1):00181\u0026ndash;2019.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStolk J, Tov N, Chapman KR, Fernandez P, MacNee W, Hopkinson NS, Piitulainen E, Seersholm N, Vogelmeier CF, Bals R, McElvaney G, Stockley RA. Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations of COPD. Eur Respir J. 2019 Nov;21(5):1900673.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePye A, Turner AM. Experimental and investigational drugs for the treatment of alpha-1 antitrypsin deficiency. Expert Opin Investig Drugs. 2019 Oct;28(10):891\u0026ndash;902.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhitters D, Stockley RA. Bronchiectasis in older patients with chronic obstructive pulmonary disease: prevalence, diagnosis and therapeutic management. Drugs Aging. 2013;30(4):215\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMart\u0026iacute;nez-Garc\u0026iacute;a MA, Miravitlles M. Bronchiectasis in COPD patients. More than a comorbidity? Int J Chron Obstruct Pulmon Dis. 2017;12:1401\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaidich DP. High-resolution computed tomography of cystic lung disease. Semin Roentgenol. 1991;26:151\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMart\u0026iacute;nez-Garc\u0026iacute;a MA, de la Rosa Carrillo D, Soler-Catalu\u0026ntilde;a JJ, et al. Prognostic value of bronchiectasis in patients with moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187(8):823\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel IS, Vlahos I, Wilkinson TMA, Loyd-Owen SJ, Donaldson GC, Wilks M, Reznek RH, Wedzicha JA. Bronchiectasis, exacerbation indices, and inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Aug 2004;15(4):400\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChalmers JD, Haworth CS, Metersky ML, Loebinger MR, Blasi F, Sibila O, O'Donnell AE, Sullivan EJ, Mange KC, Fernandez C, Zou J, Daley CL, WILLOW Investigators. ;. Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis.N Engl J Med 2020; Nov26; 383(22):2127\u0026ndash;2137.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTraversi L, Miravitlles M, Martinez-Garcia MA, et al. ROSE: radiology, obstruction, symptoms and exposure \u0026ndash; a Delphi consensus definition of the association of COPD and bronchiectasis by the EMBARC Airways Working Group. ERJ Open Res. 2021;7:00399\u0026ndash;2021.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Alpha-1 antitrypsin deficiency, Bronchiectasis, Emphysema, Prevalence","lastPublishedDoi":"10.21203/rs.3.rs-2612082/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2612082/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAlthough bronchiectasis has been recognised as a feature of some patients with Alpha1-Antitrypsin deficiency the prevalence and characteristics are not widely known. We wished to determine the prevalence of bronchiectasis and patient characteristics. The first cohort of patients recruited to the EARCO (European Alpha1 Research Collaboration) International Registry data base by the end of 2021 was analysed for radiological evidence of both emphysema and bronchiectasis as well as baseline demographic features.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the first 505 patients with the PiZZ genotype entered into the data base 418 (82.8%) had a reported CT scan. There were 77 (18.4%) with a normal scan and 38 (9.1%) with bronchiectasis alone. These 2 groups were predominantly female never smokers and had lung function in the normal range. The remaining 303 (72.5%) ZZ patients all had emphysema on the scan and 113 (27%) had additional evidence of bronchiectasis.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe data indicates the bronchiectasis alone is a feature of 9.1% of patients with the PiZZ genotype of Alpha1-antitrypsin deficiency but although emphysema is the dominant lung pathology bronchiectasis is also present in 27% of emphysema cases and may require a different treatment strategy.\u003c/p\u003e","manuscriptTitle":"The prevalence of bronchiectasis in patients with alpha-1 antitrypsin deficiency: Initial report of EARCO","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-09 23:57:57","doi":"10.21203/rs.3.rs-2612082/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2023-05-30T18:27:20+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-04-15T23:27:53+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2023-03-04T15:52:37+00:00","index":0,"fulltext":""},{"type":"editorAssigned","content":"","date":"2023-03-01T23:07:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2023-02-27T05:56:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fde941e5-015e-4412-9bc3-b02513cf73a2","owner":[],"postedDate":"March 9th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T22:06:18+00:00","versionOfRecord":{"articleIdentity":"rs-2612082","link":"https://doi.org/10.1186/s13023-023-02830-2","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2023-08-12 21:55:40","publishedOnDateReadable":"August 12th, 2023"},"versionCreatedAt":"2023-03-09 23:57:57","video":"","vorDoi":"10.1186/s13023-023-02830-2","vorDoiUrl":"https://doi.org/10.1186/s13023-023-02830-2","workflowStages":[]},"version":"v1","identity":"rs-2612082","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2612082","identity":"rs-2612082","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}