Transcript Updated approach to AECOPD - Združenje pnevmologov Slovenije

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 ?
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Respiratory rate > 35/min
Pa O2 < 5,33 kPa , pH < 7,30 inspite to NIV
Psychical deterioration
Hemodinamic instability
Inflammation in COPD Exacerbations has local and systemic effects,
induces also autoimmune and autoreactive processes.
Bacteria
Viruses
Non-infective
Pollutants
Macrophages
Epithelial
cells
TNF-
IL-8
IL-6
Neutrophils
Oxidative stress
Source: Peter J. Barnes, MD
Cells in induced Sputum
80
70
Cells (%)
60
50
Makrophages
Neutrophils
Eosinophils
Lymphozytes
40
30
20
10
0
Normal Smoker
(n=16) (n=12)
COPD Asthma
(n=14) (n=22)
Keatingset al. AJRCCM 153: 530, 1996
Changes in Lung Parenchyma after
repeated AECOPD
Alveolar wall destruction
Loss of elasticity
Destruction of pulmonary
capillary bed and loss of elastics
↑ Inflammatory cells
macrophages, CD8+ lymphocytes
Reducing the inflammation is a major
Source: Peter J. Barnes, MD
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
AECOPD
COPD patients are at increased risk for:
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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
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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 GCindividualy, 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?
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 .
Mušič 5.11.2008
Manage COPD Exacerbations
Key Points

Inhaled bronchodilators (particularly
inhaled ß2-agonists with or without
anticholinergics) and oral glucocorticosteroids 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
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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)
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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)
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Results : Bacterial species,
% of isolations
50%
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
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.
2.
3.
4.
Amoxicillin+clav.
Ciprofloxacin
Moxifloxacin
Ceftazidim
5. Ceftriaxon
6.
7.
8.
9.
Cefotaxim
Imipenem
Gentamycin
Clarithromycin
Outcome of AECOPD
• Average hospital stay
• Patients discharged improved
• Exitus letalis
10 days
122 (96,1%)
5 (3.9%)
CONCLUSIONS –Golnik 2008
In 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.
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.
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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.
Conclusion
Spead 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.