Management of acute exacerbations of COPD in 2020

Management of acute exacerbations of COPD in 2020

Mona Bafadhel

MBChB, PhD, FRCP

Associate Professor Respiratory Medicine

Consultant Respiratory Physician

University of Oxford

Objectives

1. Defining an exacerbation• Known causes

• Potential causes

2. Outcomes following an exacerbation• Following hospital admission

• Long term outcomes

3. Treatments• What the guidelines say

• What the evidence shows

4. Emerging futures

A clinical case

• MR C.• 75 year old• Ex smoker – with pack year history of 56 • Airflow limitation with FEV 43% predicted, obstructive spirometry (ratio 35%) with

significant hyperinflation (RV235%).• On triple inhaled therapy.• On mucolytics.• 3 courses of prednisolone and 2 courses of antibiotics in last 12 months• 1 episode of short hospitalisation (4 days) 1 month ago.

• Presents with worsening dyspnoea. Afebrile. Saturations 93% on air (PaO2 8.2KPa/PaCO2 4.3KPa)

• CXR: no consolidation, ECG: sinus tachycardia, No sputum

1. Defining an exacerbation

Exacerbations of COPD

• Responsible for winter bed pressures in the UK

• Cost the NHS over £500 million annually1

• Over 1.5 million GP consultations annually in UK related to exacerbation1

1. NICE

Exacerbations of COPD

• Responsible for winter bed pressures in the UK

• Cost the NHS over £500 million annually2

• Over 1.5 million GP consultations annually in UK related to exacerbation1

Definition:

‘an acute and sustained worsening of symptoms that require additional treatment’2

• Treated with systemic corticosteroids and antibiotics (unselectively)

1. NICE; 2. http://goldcopd.org;

Exacerbation definitions

• Unchanged definition for 185 years: René LaennecA Treatise on the Diseases of the Chest and on Mediate Auscultation (translated by JForbes). (‘Traité de l’’auscultation médiate et des maladies des poumons et du Coeur’).1835

Causes of an acute deterioration

• Multi-factorial– Bacteria

– Virus

– Airway inflammation

– Others– Pulmonary embolism

– Cardiac instability

– Anxiety

Bafadhel et al, AJRCCM 2011

Biologically different exacerbation clusters

IL5

TNFɑ

IFNɣ

Bafadhel et al. AJRCCM 2011: 184: 662-71

Specific biomarkers to identify exacerbation clusters

Bafadhel et al. AJRCCM 2011: 184: 662-71

2. Outcomes following an exacerbation

Outcomes following an exacerbation are poor

• In-patient mortality is as high at 10%1

• 30 and 90 day readmission rates high1

1. BTS National COPD Audit

Outcomes following an exacerbation are poor

• In patient mortality is as high at 10%1

• 30 and 90 day readmission rates high1

Survival at 5 years is between 30-50%

following a severe event2,3

1. BTS National COPD Audit; 2. Suissa et al. Thorax 2012;67: 957-963; 3. Soler-Cataluna et al. Thorax 2005; 60: 925-931

Figure adapted from Suissa S, et al. Thorax 2012;67:957–63

3. Treatments

3. Treatments

• NICE recommendations NG115 (2018)• Unless contraindicated

• Oral prednisolone 30mg for 5 days for everyone admitted to hospital

• Consider oral prednisolone (at above dose) for patients in the community where dyspnoea is affecting activity of daily living

3. Treatments

• NICE recommendations NG115 (2018)• Unless contraindicated

• Oral prednisolone 30mg for 5 days for everyone admitted to hospital

• Consider oral prednisolone (at above dose) for patients in the community where dyspnoea is affecting activity of daily living

• Consider antibiotics in the context of the following:• Severity of the symptoms, especially sputum purulence

• Previous sputum cultures and sensitivities• First, second and alternative choice of antibiotics listed in table 1 of NG114

Antibiotics in COPD exacerbations

• Cochrane review of 19 RCT’s

• Primary outcomes• Treatment failure episodes

• Secondary outcomes• Mortality, length of hospital stay, time to next exacerbation

0

10

20

30

40

50

60

70

Outpatient In-patient ICU

Setting

Setting

1. Vollenweider et al. Cochrane Database Syst Rev 2018

Primary outcome: reducing treatment failure

• Moderate exacerbations• Low quality data: RR 0.72 (95%CI, 0.56 to 94)

1. Vollenweider et al. Cochrane Database Syst Rev 2018

Primary outcome: reducing treatment failure

• Moderate exacerbations• Low quality data: RR 0.72 (95%CI, 0.56 to 94)

• Severe exacerbations• Moderate quality data: RR 0.65 (95%CI 0.38-1.12)

• Significance just reached if trials using older and no longer in clinical use (RR 0.76, 95%CI 0.58-1.00)

1. Vollenweider et al. Cochrane Database Syst Rev 2018

Primary outcome: reducing treatment failure

• Moderate exacerbations• Low quality data: RR 0.72 (95%CI, 0.56 to 94)

• Severe exacerbations• Moderate quality data: RR 0.65 (95%CI 0.38-1.12)

• Significance just reached if trials using older and no longer in clinical use (RR 0.76, 95%CI 0.58-1.00)

• ICU related exacerbations• 1 trial: RR 0.19 (95%CI 0.08-0.45)

1. Vollenweider et al. Cochrane Database Syst Rev 2018

Secondary outcomes

• Mortality and length of stay effect seen only in ICU treated exacerbations

1. Vollenweider et al. Cochrane Database Syst Rev 2018

Secondary outcomes

• Mortality and length of stay effect seen only in ICU treated exacerbations

• No effect on mortality or length of hospital stay in out-patient and in-patient exacerbations

1. Vollenweider et al. Cochrane Database Syst Rev 2018

Secondary outcomes

• Mortality and length of stay effect seen only in ICU treated exacerbations

• No effect on mortality or length of hospital stay in out-patient and in-patient exacerbations

• No studies have examined health reported outcomes

1. Vollenweider et al. Cochrane Database Syst Rev 2018

Treatment with OCS

• Established in guidance for asthma and COPD exacerbations• Prescribed to prevent treatment failure in COPD1

1. Walters et al. Cochrane Syst Review 2009

SCS for COPD exacerbations

• Primary outcomes• Treatment failure• HR 0.78 (0.63 – 0.97)

Walters et al. Cochrane Syst Review 2009

SCS for COPD exacerbations

• Primary outcomes• Treatment failure• HR 0.78 (0.63 – 0.97)

• Secondary outcomes• Improve FEV1 and symptoms (72 hours)

• 140mls (90 to 190)

Walters et al. Cochrane Syst Review 2009

SCS for COPD exacerbations

• Primary outcomes• Treatment failure• HR 0.78 (0.63 – 0.97)

• Secondary outcomes• Improve FEV1 and symptoms (72 hours)

• 140mls (90 to 190)

• Reduces length of stay by 1.22 days

• 95% CI 0.18 – 2.26

Walters et al. Cochrane Syst Review 2009

CS in COPD attacks to prevent treatment failure

Walters et al, Cochrane Syst Review 2009

8 Studies; 2 out of 8 were positive for studied outcome.• Bullard et al. Single Centre ED study in Taiwan. IV Hydrocortisone 100mg QDS

followed by 4 days IV (if admitted) or OCS if discharged vs. placebo• Thompson et al. Single centre VA (OPD and ED). 340 screened. 27 randomised.

60mg OCS 3/7, 40mg OCS for 3/7 then 20mg OCS for 3/7 vs. Vit B6

Cochrane conclusions

• COPD1

1. Walters, et al. Cochrane 2014

Systemic corticosteroids are associated with harm

• COPD exacerbations1:• NNT to prevent 1 treatment failure is 10

1. Walters et al. Cochrane Syst Review 2009

Systemic corticosteroids are associated with harm

• COPD exacerbations1:• NNT to prevent 1 treatment failure is 10

• But NNH is 5

1. Walters et al. Cochrane Syst Review 2009

Systemic corticosteroids are associated with harm

• COPD exacerbations1:• NNT to prevent 1 treatment failure is 10

• But NNH is 5

• Acute illness2:• Increased risk of Sepsis (5x), VTE (3x) and Fracture (2x)

1. Walters et al. Cochrane Syst Review 2009; 2. Waljee et al. BMJ 2018

Identification of the antibiotic responder: Is it possible?

Stockley et al. Chest 2000

SPUTUM PURULENCE

PROCALCITONIN

Sager. BMC Medicine 2017

Daniels et al. AJRCCM 2010

C REACTIVE PROTEIN

Summary

• Markers to identify who may need antibiotics have potential• CRP, purulence and purulence

• Need to be tested in prospective trials

• Evidence for antibiotics in COPD exacerbations don’t show benefit in all patients• Maybe important to identify those who need it and in whom there will be a response

Identification of the steroid responder: Is it possible?

Specific biomarkers to identify exacerbation clusters

Bafadhel et al. AJRCCM 2011: 184: 662-71

Airway eosinophilic exacerbations

Sputum eosinophilia (≥3%) present in approximately 1/3rd of exacerbations

Sputum eosinophil (%)≥3 <3

-0.3

-0.2

-0.1

0.0

∆ F

EV

1(L

)

Absolute FEV1 change

from baselinep=0.026

Absolute CRQ score change

from baseline

Sputum eosinophil (%)≥3 <3

-2.0

-1.5

-0.5

0.0

∆ C

RQ

(u

nit

s)

p=0.003

-1.0

Bafadhel et al. AJRCCM 2011: 184: 662-71

Response to steroids at exacerbation

So

ter ,

2013

Bafa

dh

el , 2011

0 .0

0 .2

0 .4

0 .6

0 .8

S tu d ie s

de

lta

FE

V (

L)

m e a n ( S D )

1. Soter et al. Inflammation 2013;36: 1178-85; 2. Bafadhel et al Am J Resp Crit Care Med 2011 184: 662-71

Sputum Eosinophils

≥3% <3%

Sputum Eosinophils

≥3% <3%

Length of stay reduced in eosinophilic exacerbations treated with corticosteroids

Mean length of stay

5.0 days (1-19)

vs.

6.5 days (1-13)

Bafadhel M. Chest 2016

Summary

• Eosinophilic exacerbations are common• Patients have bigger deficit in lung function

• Best response to SCS

4. Emerging futures

1. Redefine the acute event i. Use objective markers

2. Treatment stratificationi. Includes new treatments?

ii. Include repurposing of existing treatment

iii. Offering continuous treatment

1. Goal to redefine the event

New proposal is to call these deterioration events1

COPD crisis

Crisis is defined as

‘a time of disagreement, confusion or suffering’, ‘an extremely difficult or dangerous point in a situation’ and ‘a moment during a serious illness when there is the possibility of suddenly getting either better or worse’

1. Bafadhel et al. Lancet Respir Med 2019. In Press

1. Goal to redefine the event

New proposal is to call these deterioration events1

COPD crisis

Crisis is defined as

‘a time of disagreement, confusion or suffering’, ‘an extremely difficult or dangerous point in a situation’ and ‘a moment during a serious illness when there is the possibility of suddenly getting either better or worse’.

1. Bafadhel et al. Lancet Respir Med 2019. In Press

A new definition – The COPD Crisis1

• Crisis first coined by Hippocrates

• The turning point in the illness at which the patient or the disease prevails

1. Bafadhel et al. Lancet Respir Med 2019. In Press

A new definition – The COPD Crisis1

• Crisis first coined by Hippocrates

• The turning point in the illness at which the patient or the disease prevails

• Proposal• The crisis requires a temporal association

• Acute, protracted, resolving

• The crisis requires an underlying cause

1. Bafadhel et al. Lancet Respir Med 2019. In Press

A new definition – The COPD Crisis1

• Crisis first coined by Hippocrates

• The turning point in the illness at which the patient or the disease prevails

• Proposal• The crisis requires a temporal association

• Acute, protracted, resolving

• The crisis requires an underlying cause

1. Bafadhel et al. Lancet Respir Med 2019. In Press

COPD Crisis Temporal association Potential underlying cause (known/unknown)*

potential,

confirmed

rapid, sub-acute, protracted,

resolving

virus, bacteria, cardiac dysfunction, anxiety, social

isolation

2. Goal to target therapy in exacerbations

• STARR2 • Phase 4 multi-centre randomised clinical trial

• Near patient eosinophil testing for exacerbations of COPD)

• Study if eosinophil directed OCS is superior to standard care• Read-out Feb 2020

2. Goal to use new treatment at exacerbation events

• Utilise biological clusters to drive treatment algorithms• Antibiotic stewardship

• Novel treatments • Old therapies, new indication

• New treatments

• Acute exacerbations treated with BenRAlizumab

2. Goal to continue treatment following acute events

• Non-invasive ventilation• Improves outcomes

• Evidence demonstrates reduced mortality, reduced infections, reduced IV rates

• HOT HMV study1 – possible reduction in readmissions if Home NIV and O2 given to patients with persistent hypercapnia following discharge with acute exacerbation

1. Murphy et al,. JAMA. 2017 Jun 6; 317(21): 2177–2186

Conclusions

• The acute deteriorations of COPD are important events

• Defining these events could improve care • Rheumatology: monoclonal antibodies and OCS reduction

• Cardiology: risk scores in clinical practice

• Oncology: targeted treatment

• Understanding the COPD crisis (exacerbations) is developing • Over this new decade we should be in position to improve outcomes