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
Never smoked or not susceptible to smoke
Smoked regularly and susceptible to its effects
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75
50
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COPD: Causes And Risk Factors For Frequent Exacerbations
Exacerbations
Minimize impactReduce/delay recurrence
Thank you!