AECOPD: What Are The Causes And Risk Factors For Frequent

Exacerbations?

Camilo C. Roa, Jr., MD., FPCP, FPCCP Professor of Physiology and Medicine

UP College of Medicine - PGH

AECOPD: GOLD Definition

“An event in the natural course of the diseases characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD"

GOLD 2009

Time Course and Recovery of Exacerbations in Patients with COPD

Seemungal Am J Respir Crit Care Med 2000

101 patients mod-severe COPD studied for 2.5 yrs (when stable and during 504 exacerbations)

% Exacer-bations with

Increased Dyspnea

% Exacer-bations with

Increased Cough

Daily Median

PEFR as % Baseline

Exacerbations: Dreaded by COPD Patients

• ↑ Symptoms

• ↓ Quality of life

• ↑ Medical resource utilization (clinic/ER visits, hospitalizations, medication, oxygen use)

• ↑ Chance of dying

Long term effect: accelerated loss of lung function

Which of the following situations may indicate acute exacerbation of COPD?

1. Increased sputum volume

2. Needed to add systemic corticosteroids

3. Hospital / emergency department consult

4. Antibiotic prescription for new purulence

5. All of the above

Pathogenesis of AECOPD

Acute inflammatory events superimposed on the chronic inflammation

Exhaled breathsputumBALFBronchial biopsy

NOFibrinogenIL – 8CRPProcalcitonin

Balbi et al, ERJ 1997Sethi et al, Chest 2000Papi et al, AJRCCM 2006Zhu et al, AJRCCM 2006

Neutrophilsare attracted

into the airway lumen

AECOPD: Sputum Biomarkers

Aaron DS. AJRCCM 2001. 163:349

• C – Reactive Protein– increased in AECOPD (correlated with sputum and nasal

inflammation) (Hurst, 2005)– Increased diagnostic accuracy for AECOPD when combined

with increased dyspnea, sputum volume or purulence (Hurst, 2006)

– Increased serum levels 14 days after an exacerbation may predict future recurrent exacerbations (Perera, 2007)

• Procalcitonin– increases markedly in bacterial infections– used safely to reduce ABT use in LRTI with a low likelihood

of bacterial infection (Christ-Cain, 2004; Stolz, 2007)

• Copeptin– marker of short- and long-term prognosis in patients with

AECOPD requiring hospitalization (Soler, 2007)

AECOPD: Biomarkers

What triggers AECOPD?Environmental Factors

Volcanic AshMt. Pinatubo , Philippines1991

Smog in Shanghai, 1993

Etiology of AECB (AECOPD)

• 20% Noninfectious

– Environmental factors

– Noncompliancewith medications

• 80% Infectious

– Bacterial pathogens40%-50%

– Viral infection30%-40%

– Atypical bacteria5%-10%

Sethi S et al. Chest. 2000;117:380S

1. Advanced age

2. Severe lung function impairment

3. Persistent bronchitic symptoms like mucous production, daily cough and wheeze

4. Frequent past exacerbations

5. Heredity

From your experience, what is the most important risk factor that leads

to more frequent AECOPD?

• Increased age

• Severity of FEV1 impairment

• Chronic bronchial mucous production

• Daily cough and wheeze

• Persistent symptoms of chronic bronchitis

• Frequent past exacerbations

AECOPD: Risk Factors for Frequent Exacerbations (>2 per year)

Murata et al, 1992; Antonicelli et al, 1997; Vilkman et al, 1997; Almagro et al, 2002;

Groenemeger et al, 2003; Hodgev et al, 2004; GOLD, 2007

ECLYPSE Study: One-year Exacerbation Frequency

ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points) – a 3-yr longitudinal study with the overall objective of identifying the parameters that predict disease progression in individuals with different COPD subtypes, as well as biomarkers that may serve as surrogate end-points

No. Subjects with at least 1 exacerbation 44% 57% 69%

------------------------------------------------------------------------------------------------------------------------------

PPPY = per person per year

Vestbo. ATS Poster 2009

ECLYPSE Study: One-year Exacerbation FrequencyGold II Patients

ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points) – a 3-yr longitudinal study with the overall objective of identifying the parameters that predict disease progression in individuals with different COPD subtypes, as well as biomarkers that may serve as surrogate end-points

Vestbo. ATS Poster 2009

(Depresion)(Fatigue)

AECOPD: Chronic Cough and Sputum Production

Burgel CHEST 2009; 135:975–982

Cross-sectional analysis of data were obtained in a multicenter (17 university hospitalsin France) cohort of COPD patients. The cohort comprised 433 COPD subjects (65 +11 years;FEV1, 50 +20% predicted). Subjects with (n =321) and without (n= 112) chronic cough andsputum production were compared.

Subjects with frequent exacerbations (%)

Subjects with frequent mod. exacerbations (%)

Subjects with frequent severe exacerbations (%)

Clinical predictors of the episodes of cough and phlegm phenotype in all first-degree relatives in

the Boston Early-Onset COPD Study

Adjusted odds ratio (CL) p-value

Chronic bronchitis 5.2 (2.6–10.4) 0.0001

Self-reported pneumonia 2.3 (1.3–4.2) 0.006

Episodes of wheezing with dyspnoea

3.1 (1.7–5.7 0.0002

Active smoking 2.1 (1.2–3.9) 0.01

Number of pack-yrs 0.99 (0.98–1.01) 0.3

FEV1 post-BD % pred 0.99 (0.97–1.00) 0.1

Foreman. Eur Respir J 2007

• A 297 London COPD cohort patients were assessed for a total of 904 patient-years.

• 27 % of first exacerbations were followed by a second recurrent event within 8 weeks.

• Main Results: The observed timing distribution of second exacerbations differed significantly (P < 0.001) from the expected (random)exponential function

Hurst Am J Respir CritCare Med 2009

Temporal Clustering of Exacerbations in Chronic Obstructive Pulmonary Disease

Temporal Clustering of Exacerbations in Chronic Obstructive Pulmonary Disease

Hurst Am J Respir CritCare Med 2009

297 Patients with 1,923 interexacerbation intervals

Conclusions: Exacerbations are not random events but cluster together in time such that there is a high-risk period for recurrent exacerbation in the 8-week period after an initial exacerbation

Inflammatory changes, recovery andrecurrence at COPD exacerbation

Perera. Eur Respir J 2007; 29: 527–534

73 mod- severe COPD cases with 3.1 exacerbation/yr

Persistent Inflammation (High CRP) After n Exacerbation Is Associated With A Shorter Time To The Next Exacerbation

Perera. ERJ. Eur Respir J 2007; 29: 527–534

Relationship between serum C-reactive protein (CRP) conc. at day 14 of the index exacerbation and time to the next exacer-bation –––: rs5 -0.47, p,0.01.

Smoke and steam hangs over the volcano under the Eyjafjallajokull glacier in Iceland. Volcanic ash drifting across the Atlantic forced the cancellation of flights in Britain and disrupted air traffic across Europe.

Photograph: Jon Gustafsson/AP

COPD

COPD: Role of Bacterial Colonization

• In 20-83% of COPD pts• H flu in 60% of patients• Current smoker usually• FEV1<50% = 6X risk of

virulent GNB colonization• BAL: significant bacterial

infection of distal airways in 50% of AECB

• Colony counts higher during exacerbation

29 COPD Pts, with 51.7% colonized

– H. Influenzae (53%)

– S. pneumoniae (33%)

– H. parainflu(20%)

– B. catarrhali s(20%)

– P. aeruginosa (20%)

COPD: Bacterial Colonization and Chronic Inflammation

Patel, I S. et al. Thorax 2002;57:759

COPD: Bacterial Colonization and Frequency of Exacerbations

Relationship between lower airway bacterial colonization (LABC) by a possible pathogen in induced sputum and frequency of exacerbation Patel, et al. Thorax, 2002

“Lower airway bacterial colonization in the stable state modulates the character & freq. of COPD exacerbation”

Acquisition of New Bacterial Strains Triggers AECOPD

6. Sethi S, Sethi R, Eschberger K, et al. Am J Respir Crit Care Med 2007;176:356-61.7. Sethi S, Evans N, Grant BJB, Murphy TF. N Engl J Med 2002;347:465-71.8. Murphy TF, Brauer AL, Sethi S, Kilian M, Cai X, Lesse AJ. J Infect Dis 2007; 195:81-9.9. Murphy TF, Brauer AL, Grant BJ, Sethi S. Am J Respir Crit Care Med 2005;172:195-9.10. Murphy TF, Brauer AL, Eschberger K. Am J Respir Crit Care Med 2008;177:853-60.

NEJM 359;22 www.nejm.org Nov 27, 2008

Bacteria Role in Exacerbations Role in Stable Disease

H. influenzae 20–30% of AECOPD Major role

S. pneumoniae 10–15% of AECOPD Minor role

M. catarrhalis 10–15% of AECOPD Minor role

P. aeruginosa 5–10% of AECOPD,prevalent in advanced disease

Prob. important in advanced disease

Entero-bacteriaceae

Isolated in advanced disease, pathogenic sig. undefined

Undefined

H. haemolyticus

Isolated frequently, unlikely cause

Unlikely

H. parainfluenzae

Isolated frequently, unlikely cause

Unlikely

S. aureus Isolated infrequently, unlikely cause

Unlikely

Chronic bacterial

colonisation

Chronic inflammation

(bacterial + host-mediated inflammatory

factors)

Damaged respiratory

epithelium

Impaired host defences:

respiratory virus

new strains of bacteria

environmental irritants

Acute on chronic inflammation

(bacterial + host-mediated inflammatory factors) Progressive loss of

lung function and deteriorating quality of

life

Smoking/irritants

Chronic

cycleAcute

cycle

Pathogenesis of Exacerbations

Lower Airway Bacterial Colonization

1. It is the main reservoir of organisms that causes AECOPD

2. It is a phenomenon present in only a small minority of COPD patients

3. It prevents new pathogenic organisms from infecting the airways of COPD patients

4. It fuels persistent airway inflammation which increases the chance of an AECOPD

AECOPD: Summary

• AECOPD is a dreaded and an inevitable complication– Worsens symptoms and is potentially life threatening– Adds to the acceleration in the decline of lung function

• ↑↑ intensity of airway inflammation– most commonly caused by bacterial infection

• Risk factors associated with frequent exacerbation:– Increased age (and susceptibility to infection)– Severity of FEV1 impairment– Frequent past exacerbations– Persistent symptoms of chronic bronchitis

• Mechanism contributing to frequent exacerbation:– Failure of recovery of the airway inflammation– Persistence of trigger factor (failure to eradicate organism)

Age (years)

Disability

Death

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Smoked regularly and susceptible to its effects

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COPD: Causes And Risk Factors For Frequent Exacerbations

Exacerbations

Minimize impactReduce/delay recurrence

Thank you!