Updated approach to AECOPD

Ema Mušič

Actual objective in management of AECOPD

• To treat AECOPD properly and to reduce the frequency of such episodes.An exacerbation of COPD is defined as: “An event in the natural course of the disease

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.”

More intensive dyspnea, more sputum, sputum purulency.

Zdrav Vestn 2009;78:19-32

Therapy of AEKOPB according to severity

• Allways: smoking stopping, antibiotics in bacterial infection, th. of comorbidity

• Mild: anticholinergics, β2mimetics

• Moderate: LABA/IGC+sist.GC+Teophyllin

• Severe: +Oxygen,+/- NIV, mech. ventilation?

• When NIV? Severest dyspnea, hpoxaemia, hypercapnia

• Arrhytmia,Hypotonia, Fatigue• Somnolence• Viskosy secretion, sputum quantity

• Mech. ventilation, intubation ?• Respiratory rate > 35/min• Pa O2 < 5,33 kPa , pH < 7,30 inspite to NIV• Psychical deterioration• Hemodinamic instability

Macrophages

TNF- IL-8 IL-6

Bacteria Viruses Non-infective Pollutants

Epithelial cells

Oxidative stressOxidative stress

Neutrophils

Inflammation in COPD Exacerbations has local and systemic

effects, induces also autoimmune and autoreactive processes.

Source: Peter J. Barnes, MD

0

10

20

30

40

50

60

70

80

Normal(n=16)

Smoker

(n=12)COPD(n=14)

Asthma(n=22)

Makrophages

Neutrophils

Eosinophils

Lymphozytes

Cells in induced Sputum

Keatingset al. AJRCCM 153: 530, 1996

Ce

lls (

%)

Alveolar wall destruction

Loss of elasticity

Destruction of pulmonarycapillary bed and loss of elastics

↑ Inflammatory cells macrophages, CD8+ lymphocytes

Source: Peter J. Barnes, MD

Changes in Lung Parenchyma after repeated AECOPD

Reducing the inflammation is a major goal in COPD management

Biomarkers in AECOPD

• Irritants activate macrophages, which leads to release of cytokines* and influx of ngr. They release proteases, breaking down elastics, what leads to emphysema.

• Oxygen radicals released by ngr further damage the tissue.

• Activated epithelial cells and activated macrophages promote repair but leading to small airway fibrosis.

• Plasma Pro-adrenomedulin but not Pro-endothelin predictes survival in AECOPDin case of decreasing levels.

*IL-8, LTB4, pfosphodiesterase-4, TGF –β, TNF-α Hot Topics in Resp Med 2007:6:37-43

Chest 2008,134.263-272

BIOMARKERS-ISPs

• Spirometry and five plasma inflammation sensitive proteins measured in 5247 patients with COPD.

• Fibrinogen,ceruloplazmin, α1-antitripsin, haptoglobin, orosomucoid

• The need for hospital admmissions of AECOPD was significantly associated with the number of IPSs.

Thorax 2009;64:211-215

Oxidative stress in AECOPD

• IL-8, IL-6 and TNFα and other prooxidants are elevated in AECOPD.

• Antibiotics and systemic steroids decrese treatment failures within 30 days, but only antibiotics improve mortality of AECOPD.

FQ prolong the intervals between AECOPD (Moxifl.-MOSAIC) and lower the costs, no resistance observed until

now, using them in accordance to guidelines..

• In hypercapnic pat. with resp. acidosis and tired resp.muscles early NIMV bridges the crisis.

New research on drugs against AECOPD

• The agents against “nuclear factor kB translocation (NFkB)” ,which involves NFkB inducing kinase 2 (IKK2).

• The agents against “mitogen activated protein kinase-p38 (p38-MAPK).

• Both patways are upregulated at AECOPD in the presence of non-typable H. influenzae.

• Oxygen influence on bacterial biofilm. To long to high oxygen promote the multiplay of aerobic bacteria

COPD and Comorbidities, what has to be in mind, also in AECOPDCOPD patients are at increased risk for:

• Myocardial infarction, angina• Osteoporosis, early skin wrinkles, atherosclerosis• Respiratory infection• Depression and anxiety• Diabetes• Lung cancer

Systemic effects including:

• Weight loss

• Nutritional abnormalities

• Skeletal muscle dysfunction

Prominent studies• UPLIFT – Tiotropium reduced frequency of

AECOPD for 14%, most patients used also IGC and LABA

• T0RCH – 6112 patients on IGC+LABA: AE/year needed hospitalisation, was 0,85 on combination, in others higher. Combined COPD/asthma better on combination.

• INSPIRE- Without or less frequent infections, better on tiotropium.

• BRONCHUS- N-acetylcystein 600mg/d - AE/year lower then placebo(0,96: 1,29).

Other medications

• Mucolytics, less AE for 29%, no influence on lung function (Postgrad Med J 2009;85:141-147)

• NAC used as antioxydant.• Phoshodiesterase inhibitors. Teophyllin in low doses as

antiiflammat./immunomodulat. Agents.• New Cilomilast- Phosphodiest.inhib.-4 in dosis 2x15mg/day reduced hospitalisations

of AECOPD for 45%, without ozher therapy. (Chest 2006;129:56-66)

• Prophylactic antibiotics. Macrolides (ELECT) in GOLD III/IV + frqt AE. PULSE- Moxi 5 days/8weeks for severe COPD+frqt. AE.

• Oral bacterial extracts. Bronchomunal. Less hospitalisations, shorter hosp. days (Am J Respir Crit Care Med 1997;156:1719-1724)

• The importance of vaccination against influenza.

Current research questions

• What is the most appropriate dose if IGC?• The dose and the length of systemic GC-

individualy, not longer then 14 days.• New long acting bronchodilatators.• The addition of low dose of teophyllin to

IGC+LABA/Tiotropium.• To identify a subgroup of patients who can likely

benefit from prophylactic Ab.• Oral bacterial extracts?• Vaccination against CAP in severe COPD?

Mušič 5.11.2008

Antibiotic simply choice to Anthonissens cryteria of AECOPD.

(Symposium on COPD, Golnik 2007)

• In case of normal CRP and PCT antibiotic is not indicated PCT < 0,10mcg/L…No Ab

PCT < 0,25…..……Ab ??PCT > 0,25…...Ab !!

PCT > 0.5mcg/L…Obligatory Ab

1.Mild and moderate forms: Amoxycillin or Macrolide

2. Severe and very severe: Amoxcillin+clav. or Moxifloxacin

3. Pseudomonas : Ciprofloxacin, Ceftazidim, or both .

Manage COPD Exacerbations

Key Points

Inhaled bronchodilators

(particularly inhaled ß2-agonists

with or without anticholinergics)

and oral glucocortico- steroids

are effective treatments for

exacerbations of COPD.GC oral – for 14 days!!

Management COPD Exacerbations

Key Points

Noninvasive mechanical ventilation in exacerbations improves respiratory acidosis, increases pH, decreases the need for endotracheal intubation, and reduces PaCO2, respiratory rate, severity of breathlessness, the length of hospital stay, and mortality.

Medications and education to help prevention of future exacerbations should be considered as part of follow-up.

Possible modification of current therapy?

• Long acting β2agonists may find increasing use as rescue therapy, being combined with inhaled steroids ( TORCH, INSPIRE studies).The long acting antimuscarinic may also be as rescue th.

• New long-acting β2ag. 1x/day-Indacaterol

• Theophylline activates histondeacetylase (HDAC)- as antioxidant in AM and enhances the effects of GC.

• Macrolides are antiinflamm. in cystic fibrosis and diffuse panbronchiolitis. Also in severest stages of COPD ?.

• Anticytokines against mucus production.

How to reduce the mucin production?

• Fudostein is a novel mucoactive agent, it decreases the mucin production.

• It should inhibit MUC 5AC gene expression, being responsible for mucin hypersecretion by inhibition of some extracellular signal-related kinases.

Fluticason propionate(FP) reduces bacterial airway epithelial invasion

• FP showed reduced expression of PAFR on the surface of Pneumocytes II and bronchoepithelial cells, so bacterial load by Str. pneumoniae and H. influenzae in mice was reduced.

Eur Respir J 2008;32.1283-1288

Study Golnik 2008: SEVEREST AECOPD, CRP AND APPROPRIATE ANTIBIOTIC THERAPY. 5. Forum on

RTI, Sitges 2009

• Retrospective analysis• 127 cases of hospitalised AECOPD• AlI in GOLD stage III./IV.• Average age: 72,4 +/-9,3 years (Females-21%: 73,9+/-9,7 years, Males-79%: 71,8+/-9,2years)

• Long term oxygen treatment 43%• Sputum microbiological analysis, CRP• Expectoration inefficient in 34%• Not appropriate sputum for analysis 26%• Pathogens isolation in 40% of cases• Mostly 2-3, 30% even 4 AEKOPB last year.

BOX-AND-WHISKERS PLOT OF AGE BY

GENDER

The box represents 2I3 of cases, the length between the whiskers contains 95% of cases

CRP in patients with AECOPD 2008 (Golnik)

Results : Bacterial species, % of isolations

0%5%

10%15%20%25%30%35%40%45%50%

Updated approach to AECOPD

Ema Mušič

100% antibiotic sensitivity of isolates for:

• Pseudomonas aeruginosa : Ciprofloxacin, Ceftazidim,Imipenem,Amikacin

• H. influenzae: Amoxicillin+clav, Ciprofloxacin, Moxifloxacin

• Str. pneumoniae: Penicillin, Amoxicillin, Moxifloxacin, Amoxicillin+clav, Cephalosporins

• Moraxella catarrhalis: Amoxicillin+clav, Macrolides, Quinolons,

Cephalosporins II./III., Tri-Sul

• Enterobacteriaceae: Quinolons, Cephtasidim, Aminoglicosides

Moraxella catarrhalis and Pseudomonas aeruginosa

The sequence of the most often antibiotics in our treatment

1. Amoxicillin+clav.2. Ciprofloxacin3. Moxifloxacin4. Ceftazidim5. Ceftriaxon6. Cefotaxim7. Imipenem8. Gentamycin9. Clarithromycin

Outcome of AECOPD

• Average hospital stay 10 days

• Patients discharged improved 122 (96,1%)

• Exitus letalis 5 (3.9%)

CONCLUSIONS –Golnik 2008In severest AECOPD either Ciprofloxacin, new respiratory

Quinolons like Moxifloxacin or Amoxicillin+clav. are the best antibiotic choice.

In known risk for Pseudomonas species and Serratia infection other antipseudomonal agents, aminoglycosides or penems, combined by Ciprofloxacin should be adviced.

In case of rarely isolated Gram negative bacteria and in Staphylococcus sp. antibiotic must be chosen according to specific bacterial sensitivity in either case.

In stage III. and IV. of COPD the microbiological material from lower airways is not always possible to obtain.Therefore empiric antibiotic therapy is necessary.

Future suggestions and directions

• To search for biomarker of COPD, AECOPD.• To prevent and prolong intervals of AECOPD• To research the interactions between viruses

and bacteria: does viruses trigger the shift in strain of colonising bacteria or influence mainly on bacterial load?

• To search for receptors specific inhibitors along the inflammatory pathway.

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Management of Stable COPD and AECOPD:

Glucocorticosteroids

The dose-response relationships and long-term safety of inhaled glucocorticosteroids in COPD are not known, they are so called art of the physician.

Chronic treatment with systemic glucocorticosteroids out of AECOPD should be avoided.

Current GOLD document and the future in management

• To create on pathogenesis of inflammation oriented therapy

• To assesse the role and prevention of viral and bacterial infection.To reduce the frequency of AE

• To find the specific phenotypes for severe COPD

• To create hospital-home rehabilitation and prevention programmes

• To administer the evidence based individual and newly proven combinations of drugs.

ConclusionSpead of recovery in AECOPD and AECOPD

free intervals influence the prognosis of COPD

Next to deteriorated lung function we must be concerned with local and systemic manifestations of COPD and AECOPD, using the biomarkers of inflammated airways.

Updated suggestions for pharmacotherapy in sprays and other devices must be controlled and the patients educated home and hospitaly.