Bronchiectasis, Past, Present and FutureProfessor Adam Hill

Royal Infirmary and University of Edinburgh

NHS Education for Scotland

Plan of talk

• Diagnosis

• Aetiology

• Disease stratification

• Physiotherapy

• Long term treatments

• The future…

Bronchiectasis

1819, Laennec:

a chronic, debilitating disease

1932, Warner:

“copious foetid sputum...marked constitutional symptoms...a social outcast...”

PREVALENCE OF BRONCHIECTASIS IN THE UK FROM 2004 TO 2013

Prevalence >10 per 1,000 in the elderly

Eur Respir J 2016;47:186-193

Past

5

6

7

Score486 Patients

0 1 2 3

Bronchial dilatation

Absent Mild(lumen just > diameter of

adjacent vessel)

Moderate(lumen 2-3

times > diameter of

adjacent vessel)

Severe(lumen >3

times diameter of

adjacent vessel)

Number of bronchopulmonary segments with emphysema

Absent 1-5 >5

0

20

40

60

80

Emphysema No emphysema

Elas

tase

ng

/ml

Free Elastase

BRICS

1 MILD

2-3 MODERATE

4-5 SEVERE

Chest. 2018 153(5);1177-1186

Sputum purulence

ERJ 2009;34:361-4

N=141 MUCOID

MUCUPURULENT

PURULENT

M

I

L

D

S

E

V

E

R

E

Guides investigations, managementand clinicians to estimate prognosis

Bronchiectasis Severity Index ScoringScore range 0-26

Mild = 0-4

Moderate = 5-8

Severe = 9+

Variable Score

FEV1 % Predicted

50-80 1

30-49 2

<30 3

Hospital admission before study 5

Exacerbations before study >3 2

Dyspnoea MRC score

4 2

5 3

Pseudomonas colonization 3

Colonization with other organisms 1

Variable Score

Age

50-69 2

70-79 4

80+ 6

BMI <18.5 kg/m2 2

>3 lobes involved or cystic bronchiectasis

1

Am J Respir Crit Care Med. 2014;189:576-85

www.bronchiectasisseverity.com for online

calculation tool

0

10

20

30

40

50

60

70

80

SGRQ % Hospital admission % Mortality

Sco

re (

SGR

Q)

or

% o

f p

atie

nts

(h

osp

ital

ad

mis

sio

n a

nd

m

ort

alit

y)Mild: 0-4 Moderate: 5-8 Severe: 9+

n=191 n=224 n=193

Bronchiectasis Severity Index Scores Reflect Clinical Outcomes

12

Ref N INF IMMUNE CT ABPA CF Ciliary IBD Asp Cong No cause

1995 123 42% 4% 4% 30%

2000 150 29% 8% 3% 7% 3% 2% 1% 4% 1% 53%

2003 100 33% 1% 6% 1% 41%

2015 236 17.4% 7.1% 4.7% 3% 4.6% See CT

2.5% See CF/Cil

47.9%

2015 1258 20% 5.8% 10% 40%

Nicotra et al Chest 1995;108:955-61

Pasteur et al Am J Respir Crit Care Med 2000;162:1277-84

Kelly et al Eur J Intern Med 2003;14:488-92

Altenburg Neth J Med 2015 , VOL. 73, NO4

Lonni Ann Am Thorac Soc Vol 12, No 12, pp 1764–1770, 2015

Aetiologies with specific treatments

Cystic Fibrosis e.g. DNAase

CVID e.g. Ig replacement

Active ABPA e.g. PN, Itraconazole

Hiatus Hernia e.g. PPI, prokinetics, Sx

NTM e.g. RECl/Cipro

IBD e.g. Corticosteroids

Primary care database

Study population 18, 793

Asthma 7988 (42.5)

Chronic obstructive pulmonary disease 6774 (36.1)

HIV 1300 (6.9)

Rheumatoid arthritis 1163 (6.2)

Other connective tissue diseases 969 (5.2)

Inflammatory bowel disease 527 (2.8)

Bone marrow transplant 20 (0.11)

Hypogammaglobulinaemia 172 (0.9)

Allergic bronchopulmonary aspergillosis 339 (1.8)

None of these comorbidities 6422 (34.2)

Eur Respir J 2016;47:186-193

Comorbidities- n=986

Lancet Respir Med 2016; 4(12):969–979

Points

Metastatic malignancy 12

Haematological malignancy 6

COPD 5

Cognitive impairment 5

Inflammatory bowel disease 4

Liver disease 4

Connective tissue disease 3

Iron deficiency anaemia 3

Diabetes 3

Asthma 3

Pulmonary hypertension 3

Peripheral vascular disease 2

Ischaemic heart disease 2

3.5

11.7

34.9

0

5

10

15

20

25

30

35

40

Low Risk 0 Int Risk 1-5 High risk 6 0r >

5y MR

Low Risk 0 Int Risk 1-5 High risk 6 0r >

Lancet Respir Med 2016; 4(12):969–979

COPD with Bx, inc. risk of exacerbations

PLoS One 2016; 11(3): e0150532.

Exacerbations Mortality

Vascular disease- primary care study in 3,895,710 adults (0.3% had Bx)

CORONARY HEART DISEASERISK OF FIRST EPISODE CHD

HR 1.44 (95% CI 1.27 to 1.63)

STROKERISK OF FIRST EPISODE STROKEHR 1.71 (95% CI 1.54 to 1.90)

Thorax 2017;72:161–166.

Secondary care study (n=400)

Chest 2017;151(2):383-388

0

2

4

6

8

10

12

14

16

IHD post PVD post CVD post AF post

%

v

a

s

c

u

l

a

r

e

v

e

n

t

BSI 0-4 BSI 5-8 BSI 9+

***

**

***

Multivariable analysisRisk of vascular disease

Independent Variable

Exp(B)

95% CI P value

Male 2.39 1.14-5.02 0.02

Hypertension 2.92 1.36-6.26 0.006

On maintenance statin therapy

7.78 3.16-14.55 <0.001

BSI Moderate 5-8 3.92 1.21-12.71 0.023

BSI Severe >9 8.12 2.44-27.0 0.001

• Population based GP study- n= 895

• There was an increased rate of first time cardiovascular events in the 91 day period after a respiratory tract infection

• IRR 1.56; 95% CI 1.20 to 2.02

• The rate of a first cardiovascular event was highest in the first three days following a respiratory tract infection

• IRR 2.73, 95% CI 1.41 to 5.27

Ann Am Thorac Soc 2018 Mar;15(3):315-321

GP STUDY

Does the isolation of a pathogen matter in Bx?

Conventional Microbiology Culturepathogenic microorganisms were isolated in 75% of patientsEnvironmental mycobacteria 2-30%; Metanalysis 9.2%

Am J Respir Crit Care Med. 2012;186(7):657-65

38.6

21

12.4

11.4

9.7

9.3Haemophilus influenzae

Pseudomonas aeruginosa

Staphylococcus aureus

Moraxella catarrhalis

Streptococcus pneumoniae

Others

Arch Med Sci 2014; 10: 661-8

Ps. aeruginosaAssociated more severe disease (CT)

More rapid decline in FEV1

Increased hospitalisation + worse HRQOL

Reduced survival

Martínez-García Chest. 2007;132(5):1565-72.

Evans Eur Respir J. 1996;9(8):1601-4.

Wilson Eur Respir J. 1997;10(8):1754-60.

Miszkiel Thorax 1997;53(3):260-4.

Ho PL Chest. 1998 Dec;114(6):1594-8.

Loebinger Eur Respir J. 2009 Oct;34(4):843-9.

0

5

10

15

20

25

30

2010 2011 2012

Pseudomonas aeruginosa

2010

2011

2012

Thorax. 2012 Oct;67(10):928-30.

Thorax. 2014 Mar;69(3):292-4.

Sputum purulence

ERJ 2009;34:361-4

N=141

MUCOID

MUCUPURULENT

PURULENT

M

I

L

D

S

E

V

E

R

E

Number of out-patient exacerbations/year

*

Am J Respir Crit Care Med. 2012;186(7):657-65

27

J Clin Med. 2018 Nov; 7(11): 429.

42

21

28Am J Respir Crit Care Med. 2013 187(10): 1118–1126.

Do genetic and environmental factors influence Bx?

Vit D and Bx- 402 patients<25nmol/L deficient25-74 nmol/L insufficient>75 nmol/L replete

0102030405060708090

DeficientInsufficientReplete

*

Thorax 2013;68:39-47

*

*

2.00E+07

6.00E+06

2.00E+05

Deficient Insufficient Replete

Bacterial Load

Bact Ld

*

MBL deficiency and Bx470 Bx Pts and 414 controls

Lancet Respir Med. 2013 May;1(3):224-32

12% vs. 10% Genotype

Genotype YO/YO;XA/YO

Low

55

High

280

P

FEV1(%P) 68.9% 74.3% 0.096

Chr. colonisation

85% 65% <0.0001

Ps. aeruginosa 35% 13% <0.0001

H. Influenzae 47% 28% 0.01

Bacterial load log10 cfu/ml

6.5(2.8) 5.0(3.3) 0.01

Exacerbations 2.7(1.8) 1.9(1.3) <0.0001

SQRQ 55.4(21.9) 44.3(21.9) 0.007

LCQ 12.7(4.9) 14.3(4.4) 0.03

What long term treatments influence Bx?

Muco-active treatmentsSaline/Carbocysteine

HTA Funded Study- Belfast

380 Patients; UK; 16+ Sites

6% Saline

BDCarbocisteine

6% Saline

BD

+

C

Standard Care

rhDNAse- 349 Pts

6m. Trial

Chest. 1998 May;113(5):1329-34.

Exacerbations rhDNAse Placebo

Per patient 0.95 0.71

Inhaled Mannitol- 461 patients- 1 year- 400mg BD Vs 50mg BD Placebo

34

Mean exacerbations- 1° endpoint

Mannitol 1.69 (95% CI 1.48 to 1.94)

Control 1.84 (95% CI 1.61 to 2.10)

RR 0.92 (95% CI 0.78 to 1.08), (p=0.31)

SGRQ (0-100; MCID 4U)

Mean difference −2.40 (−4.76 to −0.05), p= 0.0457

Side Effects

16.5% failed the challenge test

82% completed study

7.2% with S/E- Cough (3.1%), ↓FEV1 (2.2%), bronchospasm (0.5%), O2desaturation (0.7%) and wheeze (0.5%).

Thorax. 2014 Dec;69(12):1073-9.

STEP 1

Offer ACBT

Review within 3m

STEP 2

If ACBT not effective/poor adherence

Consider Oscillating PEP + FET

STEP 3

Nebulised saline

(isotonic or hypertonic)

Consider Gravity Assisted Positioning

Bronchodilator

MucoactiveTx

Airway clearance

Nebulisedantibiotic/ICS

Inhaled corticosteroids in Bx- no benefit in exacs.

36Cochrane Database Syst Rev 2018

Bacterial burden in airways

3 or more exacerbations per yr

Consider long term antibiotics

No. Adult

0 20.5%

1-2 35.2%

3 or more 25.7%

No Data 18.6%

Macrolides- anti-inflammatory or anti-infective

0

0.5

1

1.5

2

2.5

3

3.5

EMBRACE 6mEMBRACE 12m BAT BLESS BLESS Pa

Active Placebo

p<0.001

p<0.003

p<0.02

p<0.0001

p<0.001

Wu Respirology 2014 Gao PLOS ONE 2014

n 530 559

Exacerbations RR 0.7 (0.6-0.82)p<0.001

RR 0.42 (0.29-0.61)P<0.001

SQRQ -5.39 (-9.89 to -0.88)P=0.02

-6.56 (-11.99 to -1.12)P=0.02

Change FEV1 0.02 (0-0.04)P=0.01

0.31 (0.12-0.51)P=0.002

Eradication Pathogens

NS

Adverse Events NS NS

EmergentPathogens

NS

GI side effects RR 3.33 (1.8-6.15)P=0.0001

Diarrhoea

Abdo pain

RR 4.47 (1.83-6.89)P=0.0001NS

RR 4.33 (1.77-10.58)P=0.001RR 6.2 (1.43-26.83), P=0.01

Chron Respir Dis. 2019 Jan-

Dec;16:1479972318790269

-0.4 Amikacin

-1.4 Colistin

-2.6 Aztreonam

-3.4 Ciprofloxacin (inh)

-4.1 Ciprofloxacin (neb)

-4.6 Tobramycin

Overall-2.75↓

Summary- reduction in cfu at 4 weeks with inhaled antibiotics

Brodt ERJ 2014;44:383-393

Time to first exacerbation

Target organism

Duration CONT Placebo Active

GentamicinN-57

PPM 80mg bd 1y Continuous1 year

Y 61d 120d*

ColomycinN-144

PA 1MU bd Continuous6 months

Y 111s103d

165d168d*

RESPIRE 1N-278

PPM 32.5mg BD Inhaled Ciprofloxacin 1y 14/28d On and Off

N 186d186d

>336d***336

RESPIRE 2N-347

PPM 1y N NE NE

ORBIT 3N- 278

PA ARD-3150 (liposome encapsulated ciprofloxacin 135 mg and free ciprofloxacin 54 mg) once daily1y

N 136d 214d

ORBIT 4N- 304

PA 1y28d On and Off

N 158d 230d*

AztreonamN- 266N- 274

Mixed 75mg tds4m28d On and Off

N 120dNE

NENE

Future- 1- Aetiology

43

Adult

Immunodeficiency IgG, IgA and IgM 75.7%

Protein

electrophoresis

61.3%

Functional antibody

response

40.1%

ABPA IgE 69.6%

Aspergillus

fumigatus RAST or

skin prick

63.1%

CF Sweat test analysis 4.1%

CF Cytogenetics 5.8%

Aspiration 3.2%

PCD 2.1%?

Future- Associated conditions + Risks

44

Airways

disease

Adult-2017

4845 patients

105 Hospitals

Asthma 29.8%

COPD 23.7%

If co-existing airways disease- Mt may be different c.f.Bx without airways diseasee.g. ICS; inhaled antibiotics

Not forgetting to optimise airways disease- Airway pharmacotherapy- Pulmonary rehabilitation- LTOT/ NIV

In moderate and severe BX- Assess vascular risk factors (smoking, weight, DM, HTN, cholesterol)- Consider secondary prevention

Future- assessing treatments for patients

Phenotyping patients better

• Sputum purulence

• Severity score e.g. Bronchiectasis Severity Index

• CT Chest Scores e.g. BRICS for idiopathic Bx

• Need CT Chest scores for other aetiologies

45

Future- assessing treatment response• Patient perspective

LCQ, SQRQ, BrQOL, Bx health Questionnaire

• Exacerbations

Mean

Number

Time to first exacerbation

• Sputum microbiology

Qualitative vs. quantitative microbiology

16S

PCR based probes

46

• Airways calibre

FEV1, FVC

Mid expiratory Flows

Multiple Breath Washout (MBW) to measure Lung Clearance Index (LCI)

• CT scanning

Assessing treatment response e.g. mucus plugging, small airways disease, quantification of emphysema, bronchial dilatation

?other modalities MRI/PET

Eur Respir J. 2015 Dec;46(6):1645-53

Future- assessing treatments quantitative responseSputum colour

47

0

10

20

30

40

50

60

70

Saline

Gentamicin

0m

3m

6m

9m

12m

0

20

40

60

80

100

neb (27) oral (88) iv (30) All (145)

% p

atie

nts

Changes in ISWT (%)

Deterioration No change 1-4.99%

5-9.99% ≧10%

Chest. 2018 Dec;154(6):1321-1329.Am J Respir Crit Care Med. 2011 15;183(4):491-9.

PAST Present Future

BTS Gx 2019First line therapy

Active Cycle Breathing Technique+

Consider Gravity Assisted Positioning

Long term antibiotics

ORAL

Systemic treatment

INHALED

Targeted treatment

Evidence base strong

In reducing exacerbations

Evidence base weaker

In reducing exacerbations

Macrolides

Gentamicin

Colomycin

Ciprofloxacin

Aztreonam

GI s/e

Balance

Resistance

Oral S/E

Bronchospasm

?Resistance

Anti-inflammatory treatmentsTreatment Duration Exacerbations Ref

AZD9668 NE inhibitor 4 weeks No evidence Respiratory Med 2013; 107:524-33.

Atorvastatin 80mg bd mild/mod Bx

6 months ↓no. but no effect on mean

Lancet Respir Med 2014;2:455-463

Atorvastatin 80mg bd severe Bx 3 months No effect Chest. 2017 Aug;152(2):368-378.

CXCR2 AZD5069 antagonist 28d No evidence Eur Respir J. 2015 Oct;46(4):1021-32.

50

Anti-inflammatory or Antibiotics or Both

Continuous vs. 14d on/off and 28d on/off

Summer break

Long term impact on resistance