Pathophysiology of Bronchiectasis

Abstract

Bronchiectasis is a complex, heterogeneous disorder defined by both a radiological abnormality of permanent bronchial dilatation and a clinical syndrome. There are multiple underlying causes including severe infections, mycobacterial disease, autoimmune conditions, hypersensitivity disorders, and genetic conditions. The pathophysiology of disease is understood in terms of interdependent concepts of chronic infection, inflammation, impaired mucociliary clearance, and structural lung damage. Neutrophilic inflammation is characteristic of the disease, with elevated levels of harmful proteases such as neutrophil elastase associated with worse outcomes. Recent data show that neutrophil extracellular trap formation may be the key mechanism leading to protease release and severe bronchiectasis. Despite the dominant of neutrophilic disease, eosinophilic subtypes are recognized and may require specific treatments. Neutrophilic inflammation is associated with elevated bacterial loads and chronic infection with organisms such as Pseudomonas aeruginosa. Loss of diversity of the normal lung microbiota and dominance of proteobacteria such as Pseudomonas and Haemophilus are features of severe bronchiectasis and link to poor outcomes. Ciliary dysfunction is also a key feature, exemplified by the rare genetic syndrome of primary ciliary dyskinesia. Mucus symptoms arise through goblet cell hyperplasia and metaplasia and reduced ciliary function through dyskinesia and loss of ciliated cells. The contribution of chronic inflammation, infection, and mucus obstruction leads to progressive structural lung damage. The heterogeneity of the disease is the most challenging aspect of management. An understanding of the pathophysiology of disease and their biomarkers can help to guide personalized medicine approaches utilizing the concept of “treatable traits.”

Keywords

bronchiectasis - inflammation - airway infection - personalized medicine

Publikationsverlauf

Artikel online veröffentlicht:
14. Juli 2021

• References

• 1 Flume PA, Chalmers JD, Olivier KN. Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity. Lancet 2018; 392 (10150): 880-890
• 2 Quint JK, Millett ER, Joshi M. et al. Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study. Eur Respir J 2016; 47 (01) 186-193
• 3 Chalmers JD, Hill AT. Mechanisms of immune dysfunction and bacterial persistence in non-cystic fibrosis bronchiectasis. Mol Immunol 2013; 55 (01) 27-34
• 4 Fuschillo S, De Felice A, Balzano G. Mucosal inflammation in idiopathic bronchiectasis: cellular and molecular mechanisms. Eur Respir J 2008; 31 (02) 396-406
• 5 Ratjen F, Waters V, Klingel M. et al. Changes in airway inflammation during pulmonary exacerbations in patients with cystic fibrosis and primary ciliary dyskinesia. Eur Respir J 2016; 47 (03) 829-836
• 6 Poppelwell L, Chalmers JD. Defining severity in non-cystic fibrosis bronchiectasis. Expert Rev Respir Med 2014; 8 (02) 249-262
• 7 Gao YH, Guan WJ, Liu SX. et al. Aetiology of bronchiectasis in adults: a systematic literature review. Respirology 2016; 21 (08) 1376-1383
• 8 Araújo D, Shteinberg M, Aliberti S. et al. Standardised classification of the aetiology of bronchiectasis using an objective algorithm. Eur Respir J 2017; 50 (06) 50
• 9 Shoemark A, Ozerovitch L, Wilson R. Aetiology in adult patients with bronchiectasis. Respir Med 2007; 101 (06) 1163-1170
• 10 Anwar GA, McDonnell MJ, Worthy SA. et al. Phenotyping adults with non-cystic fibrosis bronchiectasis: a prospective observational cohort study. Respir Med 2013; 107 (07) 1001-1007
• 11 Lonni S, Chalmers JD, Goeminne PC. et al. Etiology of non-cystic fibrosis bronchiectasis in adults and its correlation to disease severity. Ann Am Thorac Soc 2015; 12 (12) 1764-1770
• 12 Pasteur MC, Helliwell SM, Houghton SJ. et al. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med 2000; 162 (4, Pt 1): 1277-1284
• 13 Bush A, Floto RA. Pathophysiology, causes and genetics of paediatric and adult bronchiectasis. Respirology 2019; 24 (11) 1053-1062
• 14 Polverino E, Goeminne PC, McDonnell MJ. et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J 2017; 50 (03) 50
• 15 Cole PJ. Inflammation: a two-edged sword--the model of bronchiectasis. Eur J Respir Dis Suppl 1986; 147: 6-15
• 16 Stirling RG, Nicolson CH, Button BM, Wilson JW. Airway clearance in bronchiectasis: breaking the infection-inflammation cycle. Am J Respir Crit Care Med 2012; 185 (02) 226
• 17 Donovan T, Felix LM, Chalmers JD, Milan SJ, Mathioudakis AG, Spencer S. Continuous versus intermittent antibiotics for bronchiectasis. Cochrane Database Syst Rev 2018; 6: CD012733
• 18 Whitsett JA. Airway epithelial differentiation and mucociliary clearance. Ann Am Thorac Soc 2018; 15 (Suppl. 03) S143-S148
• 19 Knowles MR, Daniels LA, Davis SD, Zariwala MA, Leigh MW. Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med 2013; 188 (08) 913-922
• 20 Collins SA, Walker WT, Lucas JS. Genetic testing in the diagnosis of primary ciliary dyskinesia: state-of-the-art and future perspectives. J Clin Med 2014; 3 (02) 491-503
• 21 Mirra V, Werner C, Santamaria F. Primary ciliary dyskinesia: an update on clinical aspects, genetics, diagnosis, and future treatment strategies. Front Pediatr 2017; 5: 135
• 22 Lucas JS, Davis SD, Omran H, Shoemark A. Primary ciliary dyskinesia in the genomics age. Lancet Respir Med 2020; 8 (02) 202-216
• 23 Shah A, Shoemark A, MacNeill SJ. et al. A longitudinal study characterising a large adult primary ciliary dyskinesia population. Eur Respir J 2016; 48 (02) 441-450
• 24 Brusselle GG, Van Braeckel E. Sputum neutrophil elastase as a biomarker for disease activity in bronchiectasis. Am J Respir Crit Care Med 2017; 195 (10) 1289-1291
• 25 Shoemark A, Cant E, Carreto L. et al. A point-of-care neutrophil elastase activity assay identifies bronchiectasis severity, airway infection and risk of exacerbation. Eur Respir J 2019; 53 (06) 53
• 26 Gramegna A, Amati F, Terranova L. et al. Neutrophil elastase in bronchiectasis. Respir Res 2017; 18 (01) 211
• 27 Smallman LA, Hill SL, Stockley RA. Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect. Thorax 1984; 39 (09) 663-667
• 28 Amitani R, Wilson R, Rutman A. et al. Effects of human neutrophil elastase and Pseudomonas aeruginosa proteinases on human respiratory epithelium. Am J Respir Cell Mol Biol 1991; 4 (01) 26-32
• 29 Tosi MF, Zakem H, Berger M. Neutrophil elastase cleaves C3bi on opsonized pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch. J Clin Invest 1990; 86 (01) 300-308
• 30 Koga H, Miyahara N, Fuchimoto Y. et al. Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses. Respir Res 2013; 14: 8
• 31 Gehrig S, Duerr J, Weitnauer M. et al. Lack of neutrophil elastase reduces inflammation, mucus hypersecretion, and emphysema, but not mucus obstruction, in mice with cystic fibrosis-like lung disease. Am J Respir Crit Care Med 2014; 189 (09) 1082-1092
• 32 Gaga M, Bentley AM, Humbert M. et al. Increases in CD4+ T lymphocytes, macrophages, neutrophils and interleukin 8 positive cells in the airways of patients with bronchiectasis. Thorax 1998; 53 (08) 685-691
• 33 Nair C, Shoemark A, Chan M. et al. Cyanide levels found in infected cystic fibrosis sputum inhibit airway ciliary function. Eur Respir J 2014; 44 (05) 1253-1261
• 34 Blue E, Louie TL, Chong JX. et al; U.S. National Heart, Lung, and Blood Institute “Grand Opportunity” Exome Sequencing Project (LungGO). Variation in cilia protein genes and progression of lung disease in cystic fibrosis. Ann Am Thorac Soc 2018; 15 (04) 440-448
• 35 Szymanski EP, Leung JM, Fowler CJ. et al. Pulmonary nontuberculous mycobacterial infection: a multisystem, multigenic disease. Am J Respir Crit Care Med 2015; 192 (05) 618-628
• 36 Ramsey KA, Chen ACH, Radicioni G. et al. Airway mucus hyperconcentration in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2020; 201 (06) 661-670
• 37 Hanukoglu I, Hanukoglu A. Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene 2016; 579 (02) 95-132
• 38 Mall M, Grubb BR, Harkema JR, O'Neal WK, Boucher RC. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med 2004; 10 (05) 487-493
• 39 Azad AK, Rauh R, Vermeulen F. et al. Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease. Hum Mutat 2009; 30 (07) 1093-1103
• 40 Rademacher J, Schulz A, Hedtfeld S. et al. Nasal potential difference of carriers of the W493R ENaC variant with non-cystic fibrosis bronchiectasis. Eur Respir J 2016; 47 (01) 322-324
• 41 Fajac I, Viel M, Sublemontier S, Hubert D, Bienvenu T. Could a defective epithelial sodium channel lead to bronchiectasis. Respir Res 2008; 9: 46
• 42 Fajac I, Viel M, Gaitch N, Hubert D, Bienvenu T. Combination of ENaC and CFTR mutations may predispose to cystic fibrosis-like disease. Eur Respir J 2009; 34 (03) 772-773
• 43 Regan KH, Hill AT. Emerging therapies in adult and paediatric bronchiectasis. Respirology 2018; 23 (12) 1127-1137
• 44 Goss CH, Jain R, Seibold W. et al. An innovative phase II trial to establish proof of efficacy and optimal dose of a new inhaled epithelial sodium channel inhibitor BI 1265162 in adults and adolescents with cystic fibrosis: BALANCE-CF™ 1. ERJ Open Res 2020; 6 (04) 6
• 45 Shei RJ, Peabody JE, Kaza N, Rowe SM. The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis. Curr Opin Pharmacol 2018; 43: 152-165
• 46 King PT, Freezer NJ, Holmes PW, Holdsworth SR, Forshaw K, Sart DD. Role of CFTR mutations in adult bronchiectasis. Thorax 2004; 59 (04) 357-358
• 47 Divac A, Nikolic A, Mitic-Milikic M. et al. CFTR mutations and polymorphisms in adults with disseminated bronchiectasis: a controversial issue. Thorax 2005; 60 (01) 85
• 48 Bergougnoux A, Viart V, Miro J. et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder?. J Cyst Fibros 2015; 14 (05) 646-653
• 49 Casals T, De-Gracia J, Gallego M. et al. Bronchiectasis in adult patients: an expression of heterozygosity for CFTR gene mutations?. Clin Genet 2004; 65 (06) 490-495
• 50 Bienvenu T, Sermet-Gaudelus I, Burgel PR. et al. Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2010; 181 (10) 1078-1084
• 51 Falconer M, Collins DR, Feeney J, Torreggiani WC. Mounier-Kuhn syndrome in an older patient. Age Ageing 2008; 37 (01) 115-116
• 52 George J, Jain R, Tariq SM. CT bronchoscopy in the diagnosis of Williams-Campbell syndrome. Respirology 2006; 11 (01) 117-119
• 53 Drost N, D'silva L, Rebello R, Efthimiadis A, Hargreave FE, Nair P. Persistent sputum cellularity and neutrophils may predict bronchiectasis. Can Respir J 2011; 18 (04) 221-224
• 54 Angrill J, Agustí C, De Celis R. et al. Bronchial inflammation and colonization in patients with clinically stable bronchiectasis. Am J Respir Crit Care Med 2001; 164 (09) 1628-1632
• 55 Voglis S, Quinn K, Tullis E. et al. Human neutrophil peptides and phagocytic deficiency in bronchiectatic lungs. Am J Respir Crit Care Med 2009; 180 (02) 159-166
• 56 Watt AP, Brown V, Courtney J. et al. Neutrophil apoptosis, proinflammatory mediators and cell counts in bronchiectasis. Thorax 2004; 59 (03) 231-236
• 57 Dente FL, Bilotta M, Bartoli ML. et al. Neutrophilic bronchial inflammation correlates with clinical and functional findings in patients with noncystic fibrosis bronchiectasis. Mediators Inflamm 2015; 2015: 642503
• 58 Coman I, Pola-Bibián B, Barranco P. et al. Bronchiectasis in severe asthma: clinical features and outcomes. Ann Allergy Asthma Immunol 2018; 120: 409-413
• 59 Tsikrika S, Dimakou K, Papaioannou AI. et al. The role of non-invasive modalities for assessing inflammation in patients with non-cystic fibrosis bronchiectasis. Cytokine 2017; 99: 281-286
• 60 Tan HL, Regamey N, Brown S, Bush A, Lloyd CM, Davies JC. The Th17 pathway in cystic fibrosis lung disease. Am J Respir Crit Care Med 2011; 184 (02) 252-258
• 61 Mikami M, Llewellyn-Jones CG, Bayley D, Hill SL, Stockley RA. The chemotactic activity of sputum from patients with bronchiectasis. Am J Respir Crit Care Med 1998; 157 (3, Pt 1): 723-728
• 62 Chalmers JD, Moffitt KL, Suarez-Cuartin G. et al. Neutrophil elastase activity is associated with exacerbations and lung function decline in bronchiectasis. Am J Respir Crit Care Med 2017; 195 (10) 1384-1393
• 63 Gray RD, MacGregor G, Noble D. et al. Sputum proteomics in inflammatory and suppurative respiratory diseases. Am J Respir Crit Care Med 2008; 178 (05) 444-452
• 64 Garratt LW, Sutanto EN, Ling KM. et al; Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF). Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis. Eur Respir J 2015; 46 (02) 384-394
• 65 Keir HR, Shoemark A, Dicker AJ. et al. Neutrophil extracellular traps, disease severity, and antibiotic response in bronchiectasis: an international, observational, multicohort study. Lancet Respir Med 2021; S2213-2600 (20)30504-X
• 66 Chalmers JD, Smith MP, McHugh BJ, Doherty C, Govan JR, Hill AT. Short- and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2012; 186 (07) 657-665
• 67 Chalmers JD, Ma A, Turnbull K, Doherty C, Govan JR, Hill A. Impaired neutrophil phagocytosis and receptor expression in non-CF bronchiectasis. Eur Respir J 2013; 42: 2065
• 68 Keir HR, Fong CJ, Dicker AJ, Chalmers JD. Profile of the ProAxsis active neutrophil elastase immunoassay for precision medicine in chronic respiratory disease. Expert Rev Mol Diagn 2017; 17 (10) 875-884
• 69 King PT, Hutchinson P, Holmes PW. et al. Assessing immune function in adult bronchiectasis. Clin Exp Immunol 2006; 144 (03) 440-446
• 70 Ruchaud-Sparagano MH, Gertig H, Hester KL. et al. Effect of granulocyte-macrophage colony-stimulating factor on neutrophil function in idiopathic bronchiectasis. Respirology 2013; 18 (08) 1230-1235
• 71 Bedi P, Davidson DJ, McHugh BJ, Rossi AG, Hill AT. Blood neutrophils are reprogrammed in bronchiectasis. Am J Respir Crit Care Med 2018; 198 (07) 880-890
• 72 Gray RD, Hardisty G, Regan KH. et al. Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis. Thorax 2018; 73 (02) 134-144
• 73 Chalmers JD, Haworth CS, Metersky ML. et al; WILLOW Investigators. Phase 2 trial of the DPP-1 inhibitor brensocatib in bronchiectasis. N Engl J Med 2020; 383 (22) 2127-2137
• 74 Sibille Y, Reynolds HY. Macrophages and polymorphonuclear neutrophils in lung defense and injury. Am Rev Respir Dis 1990; 141 (02) 471-501
• 75 Zheng L, Shum H, Tipoe GL. et al. Macrophages, neutrophils and tumour necrosis factor-alpha expression in bronchiectatic airways in vivo. Respir Med 2001; 95 (10) 792-798
• 76 Fadok VA, Bratton DL, Guthrie L, Henson PM. Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: role of proteases. J Immunol 2001; 166 (11) 6847-6854
• 77 Fadok VA, Henson PM. Apoptosis: getting rid of the bodies. Curr Biol 1998; 8 (19) R693-R695
• 78 Hodge S, Upham JW, Pizzutto S. et al. Is alveolar macrophage phagocytic dysfunction in children with protracted bacterial bronchitis a forerunner to bronchiectasis?. Chest 2016; 149 (02) 508-515
• 79 Vandivier RW, Fadok VA, Hoffmann PR. et al. Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest 2002; 109 (05) 661-670
• 80 Henkle E, Curtis JR, Chen L. et al. Comparative risks of chronic inhaled corticosteroids and macrolides for bronchiectasis. Eur Respir J 2019; 54 (01) 54
• 81 Kerkhof M, Sonnappa S, Postma DS. et al. Blood eosinophil count and exacerbation risk in patients with COPD. Eur Respir J 2017; 50 (01) 50
• 82 Siva R, Green RH, Brightling CE. et al. Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Respir J 2007; 29 (05) 906-913
• 83 Martinez-Garcia MA, Posadas T, Sotgiu G, Blasi F, Saderi L, Aliberti S. Role of inhaled corticosteroids in reducing exacerbations in bronchiectasis patients with blood eosinophilia pooled post-hoc analysis of 2 randomized clinical trials. Respir Med 2020; 172: 106127
• 84 Carmier D, Dartigeas C, Mankikian J. et al. Serious bronchopulmonary involvement due to chronic lymphocytic leukaemia. Eur Respir Rev 2013; 22 (129) 416-419
• 85 Gadola SD, Moins-Teisserenc HT, Trowsdale J, Gross WL, Cerundolo V. TAP deficiency syndrome. Clin Exp Immunol 2000; 121 (02) 173-178
• 86 Holmes AH, Trotman-Dickenson B, Edwards A, Peto T, Luzzi GA. Bronchiectasis in HIV disease. Q J Med 1992; 85 (307-308): 875-882
• 87 Eden E, Choate R, Barker A. et al. The clinical features of bronchiectasis associated with alpha-1 antitrypsin deficiency, common variable immunodeficiency and primary ciliary dyskinesia--results from the U.S. Bronchiectasis Research Registry. Chronic Obstr Pulm Dis (Miami) 2019; 6 (02) 145-153
• 88 Verma N, Grimbacher B, Hurst JR. Lung disease in primary antibody deficiency. Lancet Respir Med 2015; 3 (08) 651-660
• 89 Bouvry D, Mouthon L, Brillet PY. et al; Groupe Sarcoïdose Francophone. Granulomatosis-associated common variable immunodeficiency disorder: a case-control study versus sarcoidosis. Eur Respir J 2013; 41 (01) 115-122
• 90 Jaat FG, Hasan SF, Perry A. et al. Anti-bacterial antibody and T cell responses in bronchiectasis are differentially associated with lung colonization and disease. Respir Res 2018; 19 (01) 106
• 91 Quigley KJ, Reynolds CJ, Goudet A. et al. Chronic infection by mucoid Pseudomonas aeruginosa associated with dysregulation in T-cell immunity to outer membrane porin F. Am J Respir Crit Care Med 2015; 191 (11) 1250-1264
• 92 Devalia JL, Campbell AM, Sapsford RJ. et al. Effect of nitrogen dioxide on synthesis of inflammatory cytokines expressed by human bronchial epithelial cells in vitro. Am J Respir Cell Mol Biol 1993; 9 (03) 271-278
• 93 Khair OA, Davies RJ, Devalia JL. Bacterial-induced release of inflammatory mediators by bronchial epithelial cells. Eur Respir J 1996; 9 (09) 1913-1922
• 94 López Farré A, Riesco A, Espinosa G. et al. Effect of endothelin-1 on neutrophil adhesion to endothelial cells and perfused heart. Circulation 1993; 88 (03) 1166-1171
• 95 Elferink JG, de Koster BM. Endothelin-induced activation of neutrophil migration. Biochem Pharmacol 1994; 48 (05) 865-871
• 96 Zheng L, Tipoe G, Lam WK. et al. Endothelin-1 in stable bronchiectasis. Eur Respir J 2000; 16 (01) 146-149
• 97 Humlicek AL, Pang L, Look DC. Modulation of airway inflammation and bacterial clearance by epithelial cell ICAM-1. Am J Physiol Lung Cell Mol Physiol 2004; 287 (03) L598-L607
• 98 Frick AG, Joseph TD, Pang L, Rabe AM, St Geme III JW, Look DC. Haemophilus influenzae stimulates ICAM-1 expression on respiratory epithelial cells. J Immunol 2000; 164 (08) 4185-4196
• 99 Hayashi F, Means TK, Luster AD. Toll-like receptors stimulate human neutrophil function. Blood 2003; 102 (07) 2660-2669
• 100 Look DC, Rapp SR, Keller BT, Holtzman MJ. Selective induction of intercellular adhesion molecule-1 by interferon-gamma in human airway epithelial cells. Am J Physiol 1992; 263 (1, Pt 1): L79-L87
• 101 Chalmers JD, McHugh BJ, Docherty C, Govan JR, Hill AT. Vitamin-D deficiency is associated with chronic bacterial colonisation and disease severity in bronchiectasis. Thorax 2013; 68 (01) 39-47
• 102 Sibila O, Perea L, Cantó E. et al. Antimicrobial peptides, disease severity and exacerbations in bronchiectasis. Thorax 2019; 74 (09) 835-842
• 103 Mizgerd JP, Skerrett SJ. Animal models of human pneumonia. Am J Physiol Lung Cell Mol Physiol 2008; 294 (03) L387-L398
• 104 Sibila O, Suarez-Cuartin G, Rodrigo-Troyano A. et al. Secreted mucins and airway bacterial colonization in non-CF bronchiectasis. Respirology 2015; 20 (07) 1082-1088
• 105 Tunney MM, Einarsson GG, Wei L. et al. Lung microbiota and bacterial abundance in patients with bronchiectasis when clinically stable and during exacerbation. Am J Respir Crit Care Med 2013; 187 (10) 1118-1126
• 106 Poh TY, Tiew PY, Lim AYH. et al. Increased chitotriosidase is associated with Aspergillus and frequent exacerbations in South-East Asian patients with bronchiectasis. Chest 2020; 158 (02) 512-522
• 107 Mac Aogáin M, Chandrasekaran R, Lim AYH. et al. Immunological corollary of the pulmonary mycobiome in bronchiectasis: the CAMEB study. Eur Respir J 2018; 52 (01) 52
• 108 Metersky ML, Choate R. Bronchiectasis and NTM Research Registry Investigators. The association of long-term macrolide therapy and nontuberculous mycobacterial culture positivity in patients with bronchiectasis. Chest 2021; S0012-3692 (21)00283-X
• 109 Fowler SJ, French J, Screaton NJ. et al. Nontuberculous mycobacteria in bronchiectasis: prevalence and patient characteristics. Eur Respir J 2006; 28 (06) 1204-1210
• 110 Mitchell AB, Mourad B, Buddle L, Peters MJ, Oliver BGG, Morgan LC. Viruses in bronchiectasis: a pilot study to explore the presence of community acquired respiratory viruses in stable patients and during acute exacerbations. BMC Pulm Med 2018; 18 (01) 84
• 111 Tiew PY, Jaggi TK, Chan LLY, Chotirmall SH. The airway microbiome in COPD, bronchiectasis and bronchiectasis-COPD overlap. Clin Respir J 2021; 15 (02) 123-133
• 112 Chalmers JD, Aliberti S, Filonenko A. et al. Characterization of the “frequent exacerbator phenotype” in bronchiectasis. Am J Respir Crit Care Med 2018; 197 (11) 1410-1420
• 113 Chalmers JD, Goeminne P, Aliberti S. et al. The bronchiectasis severity index: an international derivation and validation study. Am J Respir Crit Care Med 2014; 189 (05) 576-585
• 114 Hill AT, Haworth CS, Aliberti S. et al; EMBARC/BRR Definitions Working Group. Pulmonary exacerbation in adults with bronchiectasis: a consensus definition for clinical research. Eur Respir J 2017; 49 (06) 49
• 115 Choate R, Aksamit TR, Mannino D. et al. Pseudomonas aeruginosa associated with severity of non-cystic fibrosis bronchiectasis measured by the modified bronchiectasis severity score (BSI) and the FACED: The US bronchiectasis and NTM Research Registry (BRR) study. Respir Med 2020; 177: 106285
• 116 Hilliam Y, Moore MP, Lamont IL. et al. Pseudomonas aeruginosa adaptation and diversification in the non-cystic fibrosis bronchiectasis lung. Eur Respir J 2017; 49 (04) 49
• 117 Woo TE, Duong J, Jervis NM, Rabin HR, Parkins MD, Storey DG. Virulence adaptations of Pseudomonas aeruginosa isolated from patients with non-cystic fibrosis bronchiectasis. Microbiology (Reading) 2016; 162 (12) 2126-2135
• 118 Harmer C, Alnassafi K, Hu H. et al. Modulation of gene expression by Pseudomonas aeruginosa during chronic infection in the adult cystic fibrosis lung. Microbiology (Reading) 2013; 159 (Pt 11): 2354-2363
• 119 Pieterse E, Rother N, Yanginlar C, Hilbrands LB, van der Vlag J. Neutrophils discriminate between lipopolysaccharides of different bacterial sources and selectively release neutrophil extracellular traps. Front Immunol 2016; 7: 484
• 120 Martínez-Alemán S, Bustamante AE, Jimenez-Valdes RJ, González GM, Sánchez-González A. Pseudomonas aeruginosa isolates from cystic fibrosis patients induce neutrophil extracellular traps with different morphologies that could correlate with their disease severity. Int J Med Microbiol 2020; 310 (07) 151451
• 121 Rada B, Jendrysik MA, Pang L. et al. Pyocyanin-enhanced neutrophil extracellular trap formation requires the NADPH oxidase. PLoS One 2013; 8 (01) e54205
• 122 Floyd M, Winn M, Cullen C. et al. Swimming motility mediates the formation of neutrophil extracellular traps induced by flagellated Pseudomonas aeruginosa . PLoS Pathog 2016; 12 (11) e1005987
• 123 Young RL, Malcolm KC, Kret JE. et al. Neutrophil extracellular trap (NET)-mediated killing of Pseudomonas aeruginosa: evidence of acquired resistance within the CF airway, independent of CFTR. PLoS One 2011; 6 (09) e23637
• 124 Mulcahy H, Charron-Mazenod L, Lewenza S. Extracellular DNA chelates cations and induces antibiotic resistance in Pseudomonas aeruginosa biofilms. PLoS Pathog 2008; 4 (11) e1000213
• 125 Wilton M, Halverson TWR, Charron-Mazenod L, Parkins MD, Lewenza S. Secreted phosphatase and deoxyribonuclease are required by Pseudomonas aeruginosa to defend against neutrophil extracellular traps. Infect Immun 2018; 86 (09) 86
• 126 Pilsczek FH, Salina D, Poon KK. et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus . J Immunol 2010; 185 (12) 7413-7425
• 127 Juneau RA, Pang B, Weimer KE, Armbruster CE, Swords WE. Nontypeable Haemophilus influenzae initiates formation of neutrophil extracellular traps. Infect Immun 2011; 79 (01) 431-438
• 128 Murphy TF. Immunity to nontypeable Haemophilus influenzae: elucidating protective responses. Am J Respir Crit Care Med 2003; 167 (04) 486-487
• 129 Ketterer MR, Shao JQ, Hornick DB, Buscher B, Bandi VK, Apicella MA. Infection of primary human bronchial epithelial cells by Haemophilus influenzae: macropinocytosis as a mechanism of airway epithelial cell entry. Infect Immun 1999; 67 (08) 4161-4170
• 130 van Schilfgaarde M, Eijk P, Regelink A. et al. Haemophilus influenzae localized in epithelial cell layers is shielded from antibiotics and antibody-mediated bactericidal activity. Microb Pathog 1999; 26 (05) 249-262
• 131 Forsgren J, Samuelson A, Ahlin A, Jonasson J, Rynnel-Dagöö B, Lindberg A. Haemophilus influenzae resides and multiplies intracellularly in human adenoid tissue as demonstrated by in situ hybridization and bacterial viability assay. Infect Immun 1994; 62 (02) 673-679
• 132 King PT, Hutchinson PE, Johnson PD, Holmes PW, Freezer NJ, Holdsworth SR. Adaptive immunity to nontypeable Haemophilus influenzae . Am J Respir Crit Care Med 2003; 167 (04) 587-592
• 133 Dicker AJ, Crichton ML, Pumphrey EG. et al. Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 2018; 141 (01) 117-127
• 134 Taylor SL, Rogers GB, Chen AC, Burr LD, McGuckin MA, Serisier DJ. Matrix metalloproteinases vary with airway microbiota composition and lung function in non-cystic fibrosis bronchiectasis. Ann Am Thorac Soc 2015; 12 (05) 701-707
• 135 Richardson H, Dicker AJ, Barclay H, Chalmers JD. The microbiome in bronchiectasis. Eur Respir Rev 2019; 28 (153) 28
• 136 Read RC, Wilson R, Rutman A. et al. Interaction of nontypable Haemophilus influenzae with human respiratory mucosa in vitro. J Infect Dis 1991; 163 (03) 549-558
• 137 Bernstein JM, Hard R, Cui ZD, So N, Fisher J, Ogra PL. Human adenoidal organ culture: a model to study nontypable Haemophilus influenzae (NTHI) and other bacterial interactions with nasopharyngeal mucosa--implications in otitis media. Otolaryngol Head Neck Surg 1990; 103 (5, Pt 1): 784-791
• 138 Janson H, Carl n B, Cervin A. et al. Effects on the ciliated epithelium of protein D-producing and -nonproducing nontypeable Haemophilus influenzae in nasopharyngeal tissue cultures. J Infect Dis 1999; 180 (03) 737-746
• 139 Chu H, Zhao L, Xiao H. et al. Prevalence of nontuberculous mycobacteria in patients with bronchiectasis: a meta-analysis. Arch Med Sci 2014; 10 (04) 661-668
• 140 Aksamit TR, O'Donnell AE, Barker A. et al; Bronchiectasis Research Registry Consortium. Adult patients with bronchiectasis: a first look at the US Bronchiectasis Research Registry. Chest 2017; 151 (05) 982-992
• 141 Chan ED, Iseman MD. Slender, older women appear to be more susceptible to nontuberculous mycobacterial lung disease. Gend Med 2010; 7 (01) 5-18
• 142 Kartalija M, Ovrutsky AR, Bryan CL. et al. Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes. Am J Respir Crit Care Med 2013; 187 (02) 197-205
• 143 Kunst H, Wickremasinghe M, Wells A, Wilson R. Nontuberculous mycobacterial disease and Aspergillus-related lung disease in bronchiectasis. Eur Respir J 2006; 28 (02) 352-357
• 144 Griffith DE, Brown-Elliott BA, Langsjoen B. et al. Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2006; 174 (08) 928-934
• 145 Chalmers JD, Boersma W, Lonergan M. et al. Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis. Lancet Respir Med 2019; 7 (10) 845-854
• 146 Cox MJ, Turek EM, Hennessy C. et al. Longitudinal assessment of sputum microbiome by sequencing of the 16S rRNA gene in non-cystic fibrosis bronchiectasis patients. PLoS One 2017; 12 (02) e0170622
• 147 Rogers GB, van der Gast CJ, Cuthbertson L. et al. Clinical measures of disease in adult non-CF bronchiectasis correlate with airway microbiota composition. Thorax 2013; 68 (08) 731-737
• 148 Woo TE, Lim R, Heirali AA. et al. A longitudinal characterization of the non-cystic fibrosis bronchiectasis airway microbiome. Sci Rep 2019; 9 (01) 6871
• 149 Rogers GB, Bruce KD, Martin ML, Burr LD, Serisier DJ. The effect of long-term macrolide treatment on respiratory microbiota composition in non-cystic fibrosis bronchiectasis: an analysis from the randomised, double-blind, placebo-controlled BLESS trial. Lancet Respir Med 2014; 2 (12) 988-996
• 150 Zemanick ET, Sagel SD, Harris JK. The airway microbiome in cystic fibrosis and implications for treatment. Curr Opin Pediatr 2011; 23 (03) 319-324
• 151 Gao YH, Guan WJ, Xu G. et al. The role of viral infection in pulmonary exacerbations of bronchiectasis in adults: a prospective study. Chest 2015; 147 (06) 1635-1643
• 152 Lu HW, Mao B, Wei P. et al. The clinical characteristics and prognosis of ABPA are closely related to the mucus plugs in central bronchiectasis. Clin Respir J 2020; 14 (02) 140-147
• 153 Patel G, Greenberger PA. Allergic bronchopulmonary aspergillosis. Allergy Asthma Proc 2019; 40 (06) 421-424
• 154 Suarez-Cuartin G, Chalmers JD, Sibila O. Diagnostic challenges of bronchiectasis. Respir Med 2016; 116: 70-77
• 155 Ferri S, Crimi C, Campisi R. et al. Impact of asthma on bronchiectasis severity and risk of exacerbations. J Asthma 2020; 9: 1-11
• 156 De Soyza A, Pavord I, Elborn JS. et al. A randomised, placebo-controlled study of the CXCR2 antagonist AZD5069 in bronchiectasis. Eur Respir J 2015; 46 (04) 1021-1032
• 157 Lazaar AL, Miller BE, Donald AC. et al; for 205724 Investigators. CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion: a phase 2b trial. Respir Res 2020; 21 (01) 149
• 158 Konstan MW, Döring G, Heltshe SL. et al; Investigators and Coordinators of BI Trial 543.45. A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis. J Cyst Fibros 2014; 13 (02) 148-155
• 159 Döring G, Bragonzi A, Paroni M. et al. BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs. J Cyst Fibros 2014; 13 (02) 156-163
• 160 Stockley R, De Soyza A, Gunawardena K. et al. Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis. Respir Med 2013; 107 (04) 524-533
• 161 Watz H, Nagelschmitz J, Kirsten A. et al. Safety and efficacy of the human neutrophil elastase inhibitor BAY 85-8501 for the treatment of non-cystic fibrosis bronchiectasis: a randomized controlled trial. Pulm Pharmacol Ther 2019; 56: 86-93
• 162 Zhu S, Lv X, Cai W. Predictive value of blood eosinophil count in COPD. Respirology 2021; 26 (05) 504
• 163 Ko FWS, Chan KP, Ngai J. et al. Blood eosinophil count as a predictor of hospital length of stay in COPD exacerbations. Respirology 2020; 25 (03) 259-266
• 164 Hastie AT, Mauger DT, Denlinger LC. et al. Mixed sputum granulocyte longitudinal impact on lung function in the Severe Asthma Research Program. Am J Respir Crit Care Med 2021; 203 (07) 882-892
• 165 Sposato B, Scalese M, Ricci A, Rogliani P, Paggiaro P. Omalizumab Italian Study Group. Persistence of both reversible airway obstruction and higher blood eosinophils may predict lung function decline in severe asthma. Clin Respir J 2021; 15 (02) 237-243
• 166 O'Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest 1998; 113 (05) 1329-1334
• 167 Dubois AV, Gauthier A, Bréa D. et al. Influence of DNA on the activities and inhibition of neutrophil serine proteases in cystic fibrosis sputum. Am J Respir Cell Mol Biol 2012; 47 (01) 80-86
• 168 Gao YH, Abo Leyah H, Finch S. et al. Relationship between symptoms, exacerbations, and treatment response in bronchiectasis. Am J Respir Crit Care Med 2020; 201 (12) 1499-1507
• 169 Chalmers JD, Chotirmall SH. Bronchiectasis: new therapies and new perspectives. Lancet Respir Med 2018; 6 (09) 715-726
• 170 Fan LC, Liang S, Lu HW, Fei K, Xu JF. Efficiency and safety of surgical intervention to patients with non-cystic fibrosis bronchiectasis: a meta-analysis. Sci Rep 2015; 5: 17382
• 171 Ruffles TJC, Marchant JM, Masters IB. et al. Outcomes of protracted bacterial bronchitis in children: a 5-year prospective cohort study. Respirology 2021; 26 (03) 241-248
• 172 Wang G, Hallberg J, Um Bergström P. et al. Assessment of chronic bronchitis and risk factors in young adults: results from BAMSE. Eur Respir J 2021; 57 (03) 57
• 173 Sly PD, Gangell CL, Chen L. et al; AREST CF Investigators. Risk factors for bronchiectasis in children with cystic fibrosis. N Engl J Med 2013; 368 (21) 1963-1970