Bronchiectasis it s effects on the NZ population and what we can do to address this

Transcription

1 NZ Respiratory Conference Bronchiectasis it s effects on the NZ population and what we can do to address this Conroy Wong Middlemore Hospital Auckland, NZ

2 Bronchiectasis in NZ and new developments * What is bronchiectasis? * Burden of disease in NZ * Prevalence and incidence * Hospitalisations * Mortality * What can we do about it? * Bronchiectasis registries * Treatment new clinical trials * New anti-inflammatory agents

3 Rene Laennec ( ) * Invented stethoscope * 1816 * Description of bronchiectasis (1819)

4 Bronchiectasis Bronchos windpipe Ektasis - stretching N Engl J Med 2002: 346,

5 Bronchiectasis pathology and CT scans

6 Infection and inflammation * Active neutrophilic inflammation * Present even if no colonisation * Exaggerated by persistent colonisation * Associated with bacterial load * Potential to treat * Infection * Inflammation Angrill et al. AJRCCM 2001

7 Vicious cycle in bronchiectasis

8 Etiology systematic review * 56 studies * 8216 pts * Idiopathic 44.8% * Post-infective 29.9% * Immunodeficiency 5.0% * COPD 3.9% * Connective tissue dis. 3.8% * ABPA 2.6% * Ciliary dysfunction 2.5% * Asthma 1.4% * Inflammatory Bowel dis. 0.8% * Others 5.3% Gao et al. Respirology 2016

9 Role of viral infections in exacerbations * Exacerbation 49% * Coronavirus 39.2% * Rhinovirus 24.6% * Influenza 24.6% * Stable 19% Gao et al. Chest 2015

10 Prevalence and incidence in NZ * Prevalence in 2015 * 158 per 100,000 people * 686/100,000 in Pacific peoples * 368/100,000 in Maori * Incidence in 2015 * 10.8 per 100,000 * Comparison with COPD * Prevalence: 800/100,000 Incidence: 114/100,000 *Barnard and Zhang. Asthma and Respiratory Foundation report

11 Hospitalisations * Hospital admissions * Mean annual rate 25.7 per 100,000 * Bimodal distribution children and elderly * 9.1 fold higher for Pacific peoples, 4.9 fold higher for Maori * Cost 2012/13 = $5.34 million Bibby et al. NZMJ 2015

12 Hospital admissions and socioeconomic deprivation Asthma and Respiratory Foundation report

13 Bronchiectasis mortality in NZ * Mortality rates * 8.3 fold higher in Pacific peoples * 4.7 fold higher in Maori * Higher mortality if living in highly deprived areas Te Ao et al. In preparation

14 Severity and prediction of mortality Odds Ratio * FEV1 >50% vs <50% 5.19 * Age >70y vs <70y 4.98 * Pseudomonas yes vs no 2.37 * Extension >2 lobes vs * Dyspnoea mmrc 3-4 vs Martinez-Garcia et al. ERJ 2014

15 What can we do about bronchiectasis in NZ? * Find out more about bronchiectasis * More research required * Research priorities. Aliberti et al. ERJ 2016 * Factors associated with disease and progression * Particularly for Pacific and Maori populations * More and better treatment options * Main pillars of treatment physiotherapy and antibiotics * Prevention of infections * Influenza and pneumococcal vaccination * Address ethnic and socioeconomic inequalities * Overcrowding, poverty, access to healthcare

16 Bronchiectasis publications 200 Number of PubMed publications

17 Pacific Island Families Cohort * I398 Pacific children * Born in 2000 in Middlemore Hospital * Extensive data * Birthweight, smoking exposures, breast feeding, immunisations, childhood asthma, illness episodes * Parental income, education, employment * HRC funded respiratory project * Starship (Cass Byrnes), AUT (Dan Tautolo), Middlemore Hospital * Respiratory assessment ( including lung function, CXR) * Evaluate effect of early life risk factors and modifiable childhood resilience factors on respiratory outcomes

18 EMBARC European bronchiectasis registry * EMBARC formed 2012 * Funded by European Respiratory Society (50 million euros) * 10,000 patients * Important publications * BSI predictors of readmission and mortality * Phenotypes, aetiology, Pseudomonas, comorbidities, definition of exacerbation * World Bronchiectasis meetings * Australian and Indian registries Chalmers et al. Breathe 2017

19 NZ Bronchiectasis Registry * Collaboration with Australian registry (2015) * Australasian Bronchiectasis Consortium * Australian Lung Foundation * Core dataset with additional data fields for NZ * Data also linked to EMBARC database * National ethics approval * Plan to develop network across NZ

20 Management of patients * Recognise and diagnose bronchiectasis early * Education * Referral to specialist respiratory physiotherapists * Treatment of exacerbations with 2 weeks of broad spectrum antibiotics * Eradication of Pseudomonas (ERS guideline) * Pulmonary rehabilitation (ERS guideline) ERS guidelines for management. Polverino et al. Eur Resp J 2017

21 Limited evidence base for treatments of bronchiectasis Cochrane Reviews * Prolonged antibiotics Macrolides beneficial * Nebulised antibiotics Limited but new evidence * Physiotherapy Insufficient evidence * Inhaled and oral steroids Insufficient evidence * Long-acting bronchodilators Insufficient evidence * Mannitol Increased mucus clearance * Hypertonic saline Insufficient evidence * Influenza vaccine No trials * Pneumococcal vaccine Limited evidence * Nebulised DNase Harmful

22 New treatment trials * Macrolides (azithromycin, erythromycin) * Inhaled mannitol * Inhaled antibiotics * Gentamicin, Aztreonam, Colistin, Ciprofloxacin * Bronchodilators - Tiotropium * Anti-inflammatory agents * Atorvastatin * CXCR2

23 Randomised controlled trials of prolonged macrolide Rx Double-blind, placebo-controlled * EMBRACE NZ - Azithromycin * Wong et al. Lancet 2012 * BAT Netherlands - Azithromycin * Altenburg et al. JAMA 2013 * BLESS Australia - Erythromycin * Serisier et al. JAMA 2013 * BIS Australia and NZ Azithromycin * Valery et al. Lancet Resp Med 2013

24 Summary of macrolide trials * Highly effective in preventing exacerbations * 43-62% reduction in rate * Modest effects on lung function * Metaanalysis - Wu et al. Respirology 2014 * FEV1 #20 ml (0.01) * Beneficial effects on quality of life * SGRQ 5.4 u (p=0.02) * Concerns about antimicrobial resistance

25 Inhaled mannitol * Mannitol (400mg, 10 capsules, bd) vs control (50mg bd) * Treatment 1 year * N= 461 * Mannitol * No difference in exacerbation rates (primary end point) * #Median time to first exacerbation by 41 days (p=0.02) * Improved SGRQ (-2.4 units, p=0.046) * No effect on FEV1 Bilton et al. Thorax 2014

26 Inhaled antibiotics Completed and Ongoing clinical trials * Inhaled gentamicin * Murray et al. AJRCCM 2011 * Inhaled aztreonam (AIR-BX1 and AIR-BX2) * Barker et al. Lancet Respir Med 2014 * Inhaled colistin * Haworth et al. AJRCCM 2014 * Dry powder RESPIRE 1+2 ciprofloxacin * Dual release ORBIT 3+4 liposomal ciprofloxacin * Liposomal amikacin Phase 1+2 * Dry powder tobramycin Phase 1+2

27 Update on results of trials * Inhaled aztreonam both studies negative * No clinical benefit and increased adverse effects * Inhaled colistin negative for primary outcome * Positive for adherent patients (exacerbations) * Dry powder ciprofloxacin (RESPIRE) * RESPIRE 1 (14/7) beneficial, RESPIRE2 (28/7) not beneficial * Liposomal ciprofloxacin (ORBIT) * ORBIT 3 not beneficial (trend +ve), ORBIT 4 beneficial

28 ROBUST Study Reduction Of exacerbations in Bronchiectasis USing Tiotropium v Tiotropium (Spiriva) v Highly effective long-acting anticholinergic in COPD v? Effective in bronchiectasis v Design: n=90 v Multi-centre, double-blind, randomised, placebocontrolled, crossover study Tiotropium 18 µg daily Placebo 1 capsule daily Baseline Placebo 1 capsule daily Tiotropium 18 µg daily 6 months 1 month washout 6 months

29 Primary endpoints Exacerbation rates (per year) FEV Exacerbation rate Tiotropium Placebo Baseline 6 months Rate ratio 0.96 p = 0.77 Tiotropium Placebo FEV 1 difference (Tiotropium placebo) 58 mls p = 0.002

30 Atorvastatin Proof of concept trial * Atorvastatin 80mg vs placebo * Treatment for 6 months * N = 60 * Atorvastatin * # Leicester Cough Questionnaire * Mean difference 2.2 u * Secondary endpoints * serum CRP, IL-8 * # sputum neutrophil apoptosis * Increased adverse events * 10 vs 3 Mandel et al. Lancet Respir Med 2014

31 CXCR2 (IL-8 receptor) antagonist Phase 2 proof of concept study * IL-8 - potent neutrophil chemoattractant * AZD reversible * Reduces neutrophil migration * AZD5069 vs placebo, n=52 * AZD days * 69% sputum neutrophil counts * No effect on clinical outcomes De Soyza et al. ERJ 2015

32 World Bronchiectasis Conferences * 1 st : Hannover July 2016 * 2 nd : Milan July 2017 * 3 rd : Washington July 2018

33 Bronchiectasis in NZ Summary * Large and increasing burden of disease in NZ and worldwide * Particularly for Pacific and Maori populations * Research and knowledge is growing rapidly * Limited treatments available * Macrolides are effective * Potential new antibiotics and anti-inflammatory agents * Optimism for future of bronchiectasis research but uncertainty about new options for treatment

34 Acknowledgements v Catherina Chang v Chris Lewis v Alain Vandal v Lata Jayaram v Stuart Jones v David Milne v Noel Karalus v Jill Bell v Cecilia Tong v Gene Jeon v Christine Tuffery v Wendy Fergusson v Maye Hamed v Sandra Hopping v Louanne Storey v Eskandarain Shafuddin v Kathryn Askelund v Catherine Howie v Paul Dawkins v Sandra Hotu v Cass Byrnes v Adrian Trenholme v Dan Tautolo v Leon Lusitini v Health Research Council NZ v Middlemore Clinical Trials v Data Monitoring Committee of HRC