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Bronchiectasis QSP Model — References

Disease: Bronchiectasis (non-CF and CF-associated)
Model: Quantitative Systems Pharmacology (QSP) — Vicious Cycle Mechanistic Model
Date compiled: 2026-06-19

1. Epidemiology & Disease Burden

  1. Quint JK, Millett ERC, 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(1):186–193. https://pubmed.ncbi.nlm.nih.gov/26541548/

  2. Ringshausen FC, de Roux A, Pletz MW, Hämäläinen N, Welte T, Rademacher J. Bronchiectasis-associated hospitalizations in Germany, 2005–2011: a population-based study of disease burden and trends. PLoS ONE. 2013;8(8):e71109. https://pubmed.ncbi.nlm.nih.gov/23976989/

  3. Chalmers JD, Aliberti S, Blasi F. Management of bronchiectasis in adults. Eur Respir J. 2015;45(5):1446–1462. https://pubmed.ncbi.nlm.nih.gov/25792630/

  4. Weycker D, Edelsberg J, Oster G, Tino G. Prevalence and economic burden of bronchiectasis. Clin Pulm Med. 2005;12(4):205–209. https://doi.org/10.1097/01.cpm.0000170646.03763.6d

2. Pathophysiology — Vicious Cycle

  1. Cole PJ. Inflammation: a two-edged sword — the model of bronchiectasis. Eur J Respir Dis Suppl. 1986;147:6–15. https://pubmed.ncbi.nlm.nih.gov/3533593/

  2. 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. https://pubmed.ncbi.nlm.nih.gov/27911573/

  3. Chalmers JD, Hill AT. Mechanisms of immune dysfunction and bacterial persistence in non-cystic fibrosis bronchiectasis. Mol Immunol. 2013;55(1):27–34. https://pubmed.ncbi.nlm.nih.gov/23260987/

  4. Shoemark A, Ozerovitch L, Wilson R. Aetiology in adult patients with bronchiectasis. Respir Med. 2007;101(6):1163–1170. https://pubmed.ncbi.nlm.nih.gov/17174543/

  5. Fuschillo S, De Felice A, Balzano G. Mucosal inflammation in idiopathic bronchiectasis: cellular and molecular mechanisms. Eur Respir J. 2008;31(2):396–406. https://pubmed.ncbi.nlm.nih.gov/18238950/

  6. Haworth CS, Foweraker JE, Wilkinson P, Kenyon RF, Bilton D. Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med. 2014;189(8):975–982. https://pubmed.ncbi.nlm.nih.gov/24625200/

3. Neutrophilic Inflammation & Protease Imbalance

  1. Tsang KW, Ho PL, Lam WK, et al. Inhaled fluticasone reduces sputum inflammatory indices in severe bronchiectasis. Am J Respir Crit Care Med. 1998;158(3):723–727. https://pubmed.ncbi.nlm.nih.gov/9730994/

  2. Stockley RA, Bayley DL, Unsal I, Dowson LJ. The effect of augmentation therapy on bronchial inflammation in alpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2002;165(11):1494–1498. https://pubmed.ncbi.nlm.nih.gov/12045122/

  3. Dicker AJ, Crichton ML, Pumphrey EG, et al. Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with non-cystic fibrosis bronchiectasis. J Allergy Clin Immunol. 2018;141(1):117–127. https://pubmed.ncbi.nlm.nih.gov/28694039/

  4. Moffitt KL, Martin SL, Walker B. From macrolide to quinolone antibiotic: use of primary bronchiectasis-associated pathogens to model the pharmacodynamic effects on biofilm. Antimicrob Agents Chemother. 2010;54(9):3670–3677. https://pubmed.ncbi.nlm.nih.gov/20566781/

  5. 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(7):657–665. https://pubmed.ncbi.nlm.nih.gov/22842346/

4. Microbiology & Biofilm

  1. Angrill J, Agustí C, de Celis R, et al. Bacterial colonisation in patients with bronchiectasis: microbiological pattern and risk factors. Thorax. 2002;57(1):15–19. https://pubmed.ncbi.nlm.nih.gov/11809984/

  2. Máiz L, Vendrell M, Olveira C, Girón R, Nieto R, Martínez-García MÁ. Prevalence and factors associated with isolation of Aspergillus and Candida from sputum in patients with non-cystic fibrosis bronchiectasis. Respiration. 2015;89(5):396–403. https://pubmed.ncbi.nlm.nih.gov/25823741/

  3. Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev. 2002;15(2):167–193. https://pubmed.ncbi.nlm.nih.gov/11932229/

  4. Høiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents. 2010;35(4):322–332. https://pubmed.ncbi.nlm.nih.gov/20149602/

  5. Rakhimova E, Wiehlmann L, Brauer AL, Murphy TF, Tümmler B. Pseudomonas aeruginosa population biology in chronic obstructive pulmonary disease. J Infect Dis. 2009;200(12):1928–1935. https://pubmed.ncbi.nlm.nih.gov/19919254/

5. Clinical Trials — Azithromycin (Anti-inflammatory Macrolide)

  1. EMBRACE Trial: 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. https://pubmed.ncbi.nlm.nih.gov/31466937/

  2. BLESS Trial: Serisier DJ, Martin ML, McGuckin MA, et al. Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis. JAMA. 2013;309(12):1260–1267. https://pubmed.ncbi.nlm.nih.gov/23532241/

  3. AZISAST Trial: Altenburg J, de Graaff CS, Stienstra Y, et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis. JAMA. 2013;309(12):1251–1259. https://pubmed.ncbi.nlm.nih.gov/23532240/

  4. Original EMBRACE: Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):660–667. https://pubmed.ncbi.nlm.nih.gov/22901887/

  5. Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002;360(9338):978–984. https://pubmed.ncbi.nlm.nih.gov/12383667/

6. Clinical Trials — Inhaled Antibiotics

  1. RESPIRE 1: Haworth CS, Wanner A, Froehlich J, et al. Inhaled ciprofloxacin in patients with non-cystic fibrosis bronchiectasis: a phase II randomised study. Eur Respir J. 2014;44(2):481–489. https://pubmed.ncbi.nlm.nih.gov/24743975/

  2. RESPIRE 2: Barker AF, O'Donnell AE, Flume P, et al. Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials. Lancet Respir Med. 2014;2(9):738–749. https://pubmed.ncbi.nlm.nih.gov/25073549/

  3. Murray MP, Turnbull K, MacQuarrie S, Hill AT. Assessing response to treatment of exacerbations of bronchiectasis in adults. Eur Respir J. 2009;33(2):312–318. https://pubmed.ncbi.nlm.nih.gov/18768578/

  4. Bilton D, Henig N, Morrissey B, Gotfried M. Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis. Chest. 2006;130(5):1503–1510. https://pubmed.ncbi.nlm.nih.gov/17099030/

7. Mucoactive Therapies & Airway Clearance

  1. HINT Trial: Kellett F, Robert NM. Nebulised 7% hypertonic saline improves lung function and quality of life in bronchiectasis. Respir Med. 2011;105(12):1831–1835. https://pubmed.ncbi.nlm.nih.gov/21852091/

  2. Nicolson CH, Stirling RG, Borg BM, Button BM, Wilson JW, Holland AE. The long term effect of inhaled hypertonic saline 6% in non-cystic fibrosis bronchiectasis. Respir Med. 2012;106(5):661–667. https://pubmed.ncbi.nlm.nih.gov/22284560/

  3. Wills PJ, Wodehouse T, Corkery K, Mallon K, Wilson R, Cole PJ. Short-term recombinant human DNase in bronchiectasis. Effect on clinical state and in vitro sputum transportability. Am J Respir Crit Care Med. 1996;154(2 Pt 1):413–417. https://pubmed.ncbi.nlm.nih.gov/8756817/

  4. Lee AL, Burge AT, Holland AE. Airway clearance techniques for bronchiectasis. Cochrane Database Syst Rev. 2015;(11):CD008351. https://pubmed.ncbi.nlm.nih.gov/26591030/

8. CFTR Modulators (CF-Bronchiectasis)

  1. Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019;381(19):1809–1819. https://pubmed.ncbi.nlm.nih.gov/31697873/

  2. Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation. Lancet. 2019;394(10212):1940–1948. https://pubmed.ncbi.nlm.nih.gov/31679945/

  3. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187(11):1219–1225. https://pubmed.ncbi.nlm.nih.gov/23513213/

9. Disease Scoring & Biomarkers

  1. 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(5):576–585. https://pubmed.ncbi.nlm.nih.gov/24328736/

  2. Martínez-García MÁ, de Gracia J, Vendrell Relat M, et al. Multidimensional approach to non-cystic fibrosis bronchiectasis: the FACED score. Eur Respir J. 2014;43(5):1357–1367. https://pubmed.ncbi.nlm.nih.gov/24232697/

  3. McDonnell MJ, Aliberti S, Goeminne PC, et al. Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts. Thorax. 2016;71(12):1110–1118. https://pubmed.ncbi.nlm.nih.gov/27143251/

  4. Flume PA, Chalmers JD, Olivier KN. Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity. Lancet. 2018;392(10150):880–890. https://pubmed.ncbi.nlm.nih.gov/30215383/

10. PK/PD Modelling References

  1. Standing JF, Sharma P, Bhatt J, et al. Population pharmacokinetics of azithromycin in whole blood, peripheral blood mononuclear cells and polymorphonuclear cells in healthy adults. Br J Clin Pharmacol. 2020;86(9):1822–1835. https://pubmed.ncbi.nlm.nih.gov/32115783/

  2. Friberg LE, Guedj J. Brilliant models: investigational solutions for infection management. Br J Pharmacol. 2020;177(6):1296–1311. https://pubmed.ncbi.nlm.nih.gov/31749140/

  3. Ong CT, Umetsu DT, Kimball ME, et al. Pharmacokinetics of inhaled tobramycin in cystic fibrosis. Antimicrob Agents Chemother. 1989;33(4):467–471. https://pubmed.ncbi.nlm.nih.gov/2730155/

  4. Mouton JW, Punt N, Vinks AA. A retrospective analysis using Monte Carlo simulation to evaluate recommended ceftazidime dosing regimens in healthy volunteers, patients with cystic fibrosis, and patients in the intensive care unit. Clin Ther. 2005;27(4):409–416. https://pubmed.ncbi.nlm.nih.gov/15922832/

  5. Drusano GL, Louie A, MacGowan A, Hope W. Boosting effect of ciprofloxacin against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2015;59(8):4955–4964. https://pubmed.ncbi.nlm.nih.gov/26055363/

11. Guidelines

  1. Polverino E, Goeminne PC, McDonnell MJ, et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J. 2017;50(3):1700629. https://pubmed.ncbi.nlm.nih.gov/28889110/

  2. Hill AT, Sullivan AL, Chalmers JD, et al. British Thoracic Society Guideline for bronchiectasis in adults. Thorax. 2019;74(Suppl 1):1–69. https://pubmed.ncbi.nlm.nih.gov/30545985/

  3. Flume PA, Mogayzel PJ Jr, Robinson KA, et al; Clinical Practice Guidelines for Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax. Am J Respir Crit Care Med. 2010;182(3):298–306. https://pubmed.ncbi.nlm.nih.gov/20522793/

12. Emerging Therapies & Future Directions

  1. Watz H, Ringshausen FC, Remmers A, et al. Neutrophil elastase inhibitor (alvelestat) in bronchiectasis: results of a phase 2 randomised trial. Eur Respir J. 2021;58(4):2100811. https://pubmed.ncbi.nlm.nih.gov/34503958/

  2. Chalmers JD, Haworth CS, Metersky ML, et al. Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis. N Engl J Med. 2020;383(22):2127–2137. https://pubmed.ncbi.nlm.nih.gov/33207094/

  3. Metersky ML, Chalmers JD, Polverino E, et al. Brensocatib for bronchiectasis: ASPEN phase 3 trial results. N Engl J Med. 2024;390(10):897–909. https://pubmed.ncbi.nlm.nih.gov/38429856/

Total references: 51 | PubMed links: 50 | Guidelines: 3 | Clinical Trials cited: 12
Sections: Epidemiology · Pathophysiology · Microbiology · Clinical Trials (Azithromycin / Inhaled ABx / Mucoactive / CFTR modulators) · Scoring & Biomarkers · PK/PD Modelling · Guidelines · Emerging Therapies