Antibiotic in COPD.ppt

Antibiotics in Chronic Obstructive
Pulmonary Disease

Summary of Topics
• COPD overview
• Epidemiology, definition, and pathogenesis
• Current research
• Current guidelines
• Application of research data
• Future directions
2

Revised Definition
Summary of GOLD 2017 Update: For Educational Purpose Only 3

“ Chronic Obstructive Pulmonary
Disease (COPD), a common
preventable and treatable disease,
is characterized by persistent
airflow limitation that is usually
progressive and associated with
an enhanced chronic
inflammatory response in the
airways and the lung to noxious
particles or gases. Exacerbations
and comorbidities contribute to
the overall severity in individual
patients.”
GOLD 2016 GOLD 2017
“ Chronic Obstructive Pulmonary
Disease (COPD) is a common,
preventable and treatable disease
that is characterized by persistent
respiratory symptoms and airflow
limitation that is due to airway and/
or alveolar abnormalities usually
caused by significant exposure to
noxious particles or gases”
4

5th
leading
cause of
loss of
DALYs
The revised burden of COPD
• The global prevalence of COPD is 11.7%
• Currently 3 million annual deaths due to COPD. The deaths in 2030 might be 4.5
million deaths annually.
• DALYs: Disability adjusted life years
• One DALY represents the loss of the equivalent of one year of full health
• COPD is leading cause of loss of DALYs across the world.
6
8th
leading
cause of
loss of
DALYs
2005 2013

The fourth leading cause of death in the
United States is:
a)Heart disease
b)Cancer
c)Chronic obstructive pulmonary disease (COPD)
d)Cerebrovascular accidents
7

Factors which influence the development &
progression of disease
• Genetic
• Age and Gender
• Lung Growth and development
• Socioeconomic Status
• Exposure to particles
• Tobacco Smoking
• Occupational Exposure
• Biomass
• High levels of Urban Air Pollution
• Asthma and Airway hyper-reactivity
• Chronic bronchitis
•Infections

Infections
•Severe childhood respiratory infections
•HIV infection accelerates onset of smoking related
emphysema and COPD
•Tuberculosis has been identified as a risk factor for
COPD
• TB is a differential diagnosis and potential comorbidity

Stable COPD
•Chronic disease
•Loss of lung function
•Airflow limitation and abnormal inflammatory
response
• Diagnosis based on:
• Symptoms
• History of exposure: tobacco smoke, occupational dusts and
chemicals
• Spirometry
10
Williams DM, Bourdet SV. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds.
Pharmacotherapy: a pathophysiologic approach. 7th ed. McGraw-Hill Companies, Inc; 2008: 495-499.

Antibiotics
• Naturally occurring antimicrobials
•Metabolic products of bacteria and fungi
•Reduce competition for nutrients and space
• Bacteria that produce them:
• Streptomyces, Bacillus,
• Molds
•Penicillium, Cephalosporium

Different classes of antibiotics
13

Prophylactic Use of Macrolide Antibiotics for the Prevention of
Chronic Obstructive Pulmonary Disease Exacerbation: A Meta-
Analysis - DOI:10.1371/journal.pone.0121257 March 26, 2015
• Acute exacerbations of chronic obstructive pulmonary disease
(AECOPDs) can lead to high frequencies and rates of hospitalization and
mortality. Macrolides are a class of antibiotics that possess both
antimicrobial and anti-inflammatory properties. Since the occurrence of
AECOPDs is associated with aggravation of airway inflammation and
bacterial infections, prophylactic macrolide treatment may be an
effective approach towards the prevention of AECOPDs.
• Methods - We systemically searched the PubMed, Embase and Cochrane
Library databases to identify randomized controlled trials (RCTs) that
evaluated the effect of prophylactic macrolide therapy on the prevention
of AECOPDs. The primary outcomes were the total number of patients
with one or more exacerbations as well as the rate of exacerbations per
patient per year.
16

Prophylactic Use of Macrolide Antibiotics for the Prevention of
Chronic Obstructive Pulmonary Disease Exacerbation: A Meta-
Analysis - DOI:10.1371/journal.pone.0121257 March 26, 2015
• Results - Nine RCTs comprising 1666 patients met the inclusion criteria.
Pooled evidence showed macrolides could reduce the frequency of
exacerbations in patients with COPD by both unweighted (RR = 0.70;
95% CI: 0.56–0.87; P < 0.01) and weighted approaches (RR = 0.58, 95%
CI: 0.43–0.78, P < 0.01). Subgroup analysis showed only 6–12 months of
erythromycin or azithromycin therapy could be effective.
• Conclusions - Our results suggest 6-12 months erythromycin or
azithromycin therapy could effectively reduce the frequency of
exacerbations in patients with COPD. However, Long-term treatment
may bring increased adverse events and the emergence of macrolide-
resistance. A recommendation for the prophylactic use of macrolide
therapy should weigh both the advantages and disadvantages.
17

The effect of oral clarithromycin on health status
and sputum bacteriology in stable COPD
• Background: Chronic obstructive pulmonary disease (COPD) is
characterised by airway inflammation, poor health status and recurrent
infective exacerbations. Macrolide antibiotics have been shown to
improve symptoms and exacerbation rate in chronic lung disease,
particularly cystic fibrosis (CF) and diffuse pan-bronchiolitis. The effect of
long-term oral clarithromycin on health status, sputum bacterial
numbers and exacerbation rate in subjects with clinically stable COPD is
undetermined.
• Methods: Subjects with moderate-to-severe COPD were recruited into a
prospective, double-blind, randomised-controlled trial of 3-months oral
clarithromycin (Klaricid XL) or placebo once-daily. The effect of
clarithromycin on health status (St. George respiratory and Short Form-
36 questionnaires), sputum quantitative bacterial numbers and
exacerbation rate were investigated.
18

The effect of oral clarithromycin on health status
and sputum bacteriology in stable COPD
• Results: Sixty-seven subjects (46 males) were recruited; 31 and 36
subjects
• received clarithromycin and placebo, respectively. There were 7(10%)
withdrawals. Compared to placebo, clarithromycin did not significantly
improve health status, sputum bacterial numbers, or exacerbation rate.
• Conclusions: Three months of oral clarithromycin given to subjects with
stable COPD does not improve health status, sputum bacterial numbers
or exacerbation rate. Treatment of COPD with clarithromycin during the
clinical stable state yields no clinical advantages and therefore cannot be
recommended as means of eliminating sputum bacteria or preventing
infective exacerbations.
19

Effects of different antibiotic classes on airway
bacteria in stable COPD using culture and molecular
techniques: a randomised controlled trial
• Background - Long-term antibiotic therapy is used to prevent
exacerbations of COPD but there is uncertainty over whether this
reduces airway bacteria. The optimum antibiotic choice remains
unknown. We conducted an exploratory trial in stable patients with
COPD comparing three antibiotic regimens against placebo.
• Methods This was a single-centre, single-blind, randomised placebo-
controlled trial. Patients aged ≥45 years with COPD, FEV1<80% predicted
and chronic productive cough were randomised to receive either
moxifloxacin 400 mg daily for 5 days every 4 weeks, doxycycline 100
mg/day, azithromycin 250 mg 3 times a week or one placebo tablet daily
for 13 weeks. The primary outcome was the change in total cultured
bacterial load in sputum from baseline; secondary outcomes included
bacterial load by 16S quantitative PCR (qPCR), sputum inflammation and
antibiotic resistance.
20

• Results - 99 patients were randomised; 86 completed follow-up, were
able to expectorate sputum and were analysed. After adjustment, there
was a non-significant reduction in bacterial load of 0.42 log10 cfu/mL
(95% CI −0.08 to 0.91, p=0.10) with moxifloxacin, 0.11 (−0.33 to 0.55,
p=0.62) with doxycycline and 0.08 (−0.38 to 0.54, p=0.73) with
azithromycin from placebo, respectively. There were also no significant
changes in bacterial load measured by 16S qPCR or in airway
inflammation. More treatment-related adverse events occurred with
moxifloxacin. Of note, mean inhibitory concentrations of cultured
isolates increased by at least three times over placebo in all treatment
arms.
• Conclusions - Total airway bacterial load did not decrease significantly
after 3 months of antibiotic therapy. Large increases in antibiotic
resistance were seen in all treatment groups and this has important
implications for future studies.
21

• What is the key question?
• ▸ How do three different antibiotics (moxifloxacin, doxycycline and
azithromycin) compare in their effects on total airway bacterial load in
stable COPD?
• What is the bottom line?
• ▸ Airway bacterial load was similar to placebo after treatment with all
three antibiotics, although increases in antimicrobial resistance were
noted in all treatment arms.
• Why read on?
• ▸ This is the first trial to directly compare the effects of different
antibiotic classes on airway bacterial load in stable COPD.
22

Exacerbation of COPD
•Acute change in baseline symptoms:
• Dyspnea, cough, and/or sputum production
•Consequences:
• Decreased quality of life
• Accelerated lung function decline
• Increased mortality
• Increased resource utilization and costs
23
Williams DM, Bourdet SV. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a
pathophysiologic approach. 7th ed. McGraw-Hill Companies, Inc; 2008: 495-499.
Can Respir J 2008;15 (Suppl A):1A-8A.

Exacerbations and lung function decline
• The difference in the decline in
FEV1 between the infrequent and
frequent exacerbators was 8
ml/year, and their median
exacerbation rates were 1.9 and
4.2 per year
• PEF did not recover to pre-
exacerbation levels within 91
days in 7.1% of exacerbations.

Exacerbations
•Median number of exacerbations seen in primary
care was two per year, with one in three suffering
three or more exacerbations in 1 year
•Frequent exacerbators (> 2 per year):
•Chronic sputum producers
•Housebound
•Frequent colds
•Poor quality of life
•Raised inflammatory markers when stable

Exacerbation: Goals of Therapy
•Prevention of hospitalization or reduction in
hospital stay
•Prevention of acute respiratory failure and death
•Resolution of symptoms
•Return to baseline
26
Williams DM, Bourdet SV. Chronic Obstructive Pulmonary Disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a
pathophysiologic approach. 7th ed. McGraw-Hill Companies, Inc; 2008: 495-499.

Etiology of COPD Exacerbations
28
Infectious Noninfectious
~20% Mucoid
Sputum
Viral
~40-50%
Atypical
~5-10%
Bacterial-viral co-
infection may occur
Bacterial
~40-50%
Allergies, smoking,
pollution, stress;
undertreatment or
nonadherence in
established COPD
Anzueto A. Primary care management of chronic obstructive
pulmonary disease to reduce exacerbations and their
consequences. Am J Med Sci. 2010;340(4):309-318.
Purulent
Sputum

Bar chart representing the mean factor scores for the three identified biologic factors (proinflammatory, Th1, and Th 2) categorized according to the
four biologic clusters. (B) Proportional representation of biologic chronic obstructive pulmonary disease exacerbation clusters in three-dimensional
ellipsoids. Cluster 1 is termed “bacteria-predominant” and is outlined in blue, cluster 2 is termed “eosinophil-predominant” and is outlined in green,
cluster 3 is termed “virus-predominant” and is outlined in red, and cluster 4 is termed “pauciinflammatory” and is outlined in gray.
Am J Respir Crit Care Med,
https://www.atsjournals.org/doi/abs/10.1164/rccm.201104-0597OC

Bacteria as a Cause of Exacerbation
•Common bacteria:
• Haemophilus influenzae
• Streptococcus pneumoniae
• Moraxella catarrhalis
• Pseudomonas aeruginosa
•Indicators of bacterial infection
• Bronchoscopic sampling in pooled analysis of studies
• Purulent sputum
31
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med.
2008;359:22.

Proposed Model of Pathogenesis
32
Acquire new
bacterial strain
Change in
airway/systemic
inflammation
Pathogen virulence
Host lung defense
Increased
respiratory
symptoms
Strain-specific
immune response,
+/- Antibiotics
Elimination of
infecting strain
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med.
2008;359:22.

33
Adapted from Sethi S, Murphy TF. Infection in the
pathogenesis and course of chronic obstructive pulmonary
disease. N Engl J Med . 2008;359:22.
Innate Lung Defense
• Disruption of innate lung
defense
• Impaired mucociliary
clearance
• Impaired phagocytosis of
alveolar macrophage
• Epithelial cells as physical
barrier and orchestrators of
host defense

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.

COPD Exacerbation Treatment:
Role of Antibiotics
35

Exacerbation Treatment
• Oxygen therapy
•  Dose/frequency of bronchodilators
• Glucocorticosteroids
• Mechanical ventilation
36
• Antibiotics
Global Strategy for the Diagnosis, Management and Prevention of COPD, 2010. Available from:
http://www.goldcopd.org.

Controversy Over Antibiotic Use
• Overuse can lead to resistance
• 20% of exacerbations are noninfectious
• Mixed results from studies
37

Ofloxacin vs. Placebo
• Study design: Prospective randomized controlled trial
• Objective
• Therapy: ofloxacin vs. placebo
• Primary outcome measures
39
Nouira S, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation
requiring mechanical ventilation; a randomised placebo-controlled trial. Lancet. 2001;358:2020-25.

Results
40
Nouira S, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation
requiring mechanical ventilation; a randomised placebo-controlled trial. Lancet. 2001;358:2020-25.
Outcome
Measure
Ofloxacin
(n=47)
Placebo
(n=46)
Absolute Risk
Reduction
(95% CI)
P Value
ICU death 2(4%) 8(17%) 13.2(0.8 to 25.6) 0.05
Hospital
death
2(4%) 10(22%) 17.5(4.3 to 30.7) 0.01
Need for
additional
antibiotics
3(6%) 16(35%) 28.4(12.9 to 43.9) 0.0006
Combined
events
5(11%) 26(57%) 45.9(29.1 to 62.7) <0.0001

Doxycycline vs. Placebo
• Study design: Prospective randomized controlled trial
• Objective
• Therapy: doxycycline vs. placebo
• Primary and secondary outcome measures
41
Daniels, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic
obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:150-157.

Results
Outcome Measure Doxycycline
(n=128)
Placebo
(n=137)
Odds Ratio or
Mean Difference
(95% CI)
P Value
Clinical success on Day 10,
no. (%)
103(80) 94(69) 1.9(1.1 to 3.2) 0.03
Clinical cure on Day 10,
no. (%)
86(67) 69(51) 1.9(1.2 to 3.2) 0.01
Clinical success on Day 30,
no. (%)
78(61) 72(53) 1.3(0.8 to 2.0) 0.32
Clinical cure on Day 30,
no. (%)
65(51) 56(41) 1.4(0.9 to 2.3) 0.15
42
Daniels, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of
chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:150-157.

Early Antibiotic Administration
•Study design: Retrospective cohort
•Objective
•Primary and secondary outcome measures
43
Rothberg MB, et al. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of
chronic obstructive pulmonary disease. JAMA. May 2010;303(20):2035-2042.

Cohort Study Design
44
Treatment
Failure
No
Treatment
Failure
Treatment
Failure
No
Treatment
Failure
Study design. Duke University Medical Center Library.
http://www.mclibrary.duke.edu/subject/ebm/studies.html. last modified 8-26-2008. (Accessed 2-28-2011).

Results
Model Odds Ratio
(95% CI)
Unadjusted 0.82
(0.78-0.87)
Adjusted 0.87
(0.82-0.92)
45
Rothberg MB, et al. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic
obstructive pulmonary disease. JAMA. May 2010;303(20):2035-2042.
Outcome
Measure
Adjusted Ratio
(95% CI)
Length of
stay
1.03
(1.02-1.04)
Cost 1.03
(1.02-1.04)
Treatment Failure Length of Stay & Cost

Non-Hospitalized Exacerbation Patients
•Study design: Systematic review
•Objective
•Study subjects
46
Ram FSF, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease (Review). Cochrane
Database Sys. Rev. (2): CD004403, 2006.

Results
Outcome Measure Relative Risk
Reduction
Relative Risk
(95% CI)
Mortality 77% 0.23(0.10-0.52)
Sputum purulence 48% 0.52(0.37-0.72)
Treatment failure
(Hospital-based trials)
53% 0.47(0.36-0.62)
Treatment failure
(Community-based trials)
- 0.91(0.70-1.18)
47
Ram FSF, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease (Review). Cochrane
Database Sys. Rev. (2): CD004403, 2006.

Antibiotics
• Background
Van Velzen et al, 2017

Antibiotics
Van Velzen et al, 2017

GOLD Guidelines
Antibiotics should be given to patients with:
• All 3 cardinal symptoms:
•  dyspnea
•  sputum volume
•  sputum purulence
• 2 of the cardinal symptoms if  sputum purulence included
• Severe exacerbation requiring mechanical ventilation
52
Global Strategy for the Diagnosis, Management and Prevention of COPD, 2010. Available from: http://www.goldcopd.org.

Classification of Exacerbations Introduced in GOLD
2017
According to GOLD 2017, exacerbations are now classified as:
GOLD 2017 Update 53
Type of
Exacerbation
If treated with
Mild Only SABD
Moderate SABD + Antibiotics and/or Oral Corticosteroids
Severe Patient requires hospitalization or has an emergency
room visit
SABD: Short Acting Bronchodilators

Antibiotics
ERS/ATS Statement 2017
•Antibiotic therapy decreased treatment failure from
42% to 28% (RR 0.67) - therefore NNT to prevent
one treatment failure is 7
•The majority (58%) of patients improved without
antibiotics, suggesting not all exacerbations require
antibiotics

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 .

Application of Research Data
• Continue to use antibiotics in severe exacerbations requiring
mechanical ventilation
• Limit antibiotic use to those patients requiring hospitalization for
their exacerbation
• Administer antibiotics early, if necessary, within first 2 days of
hospital admission
58

Biomarker guided:
Serum C-Reactive Protein (CRP) Guidance
Outcome Measure N (%) P Value
Serum CRP of >50 mg/L
on Day 10
109 (41%) 0.01
Serum CRP of >50 mg/L
on Day 30
109 (41%)) 0.04
Serum CRP of <50 mg/L
on Day 10
156 (59%) 0.53
Serum CRP of <50 mg/L
on Day 30
156 (59%) 0.75
59
Subgroup Analysis in Doxycycline Study
Daniels, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of
chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;181:150-157.

Biomarker guided:
Procalcitonin Guidance
Outcome
Measure
Relative Risk
(95% CI)
P Value
Antibiotic
exposure
0.56 (0.43-0.73) <0.0001
60
• Randomized controlled trial
• Standard therapy group vs. procalcitonin group
• Equivalent clinical success rate (p = 0.853)
Stolz D, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-
guidance with standard therapy. Chest 2007;131:9-19.

Antiobiotics
Which antibiotics to use?
• Targeted towards previous sputum results
Moraxella commonly found, Haemophilus may need
longer courses (2 weeks), if Pseudomonas isolated > 1
occasion seek respiratory advice
• What the patient usually responds to
• Otherwise:
Amoxicillin 500mg TDS, Co-Amoxiclav 625mg TDS,
Doxycyxline 100mg OD, Clarithromycin 500mg BD

Summary
Who to give antibiotics to?
Unwell, sputum purulence, CRP
> 40
• Who to admit?
Inability to manage at home,
severe SOB, developing
peripheral oedema, hypoxic
Differential diagnoses
• PTX
• Pneumonia
• Pulmonary emboli
• Myocardial infarction and arrhythmia
Working towards biomarker-directed approach

Antibiotics
Point of care CRP
• In the placebo arm, 77% of CRP tests
resulted in concentrations < 40
mg/L.
• If CRP < 40, the failure rate was
12.4%
• If CRP > 40, the failure rate was
65.5% (P < 0.001)
Miratvalles, 2013

Antibiotics
The only factors
significantly associated with
an increased risk of failure
without antibiotics were
the increase in sputum
purulence (OR, 6.1) and a
CRP concentration ≥ 40
mg/L (OR, 13.4). When
both factors were present,
the probability of failure
without antibiotics was
63.7%.
Predictive value for clinical failure of
Anthonisen criteria (dotted line) (AUC
0.708) and with the addition of a C-
reactive protein level ≥ 40 mg/L (solid
line) (AUC 0.842) among patients with
exacerbations of mild to moderate COPD
not treated with antibiotics.

The Four Moments of Antibiotic Decision
Making
1. Does my patient have an infection that
requires antibiotics?
68

Moment 1: Distinguishing a COPD Exacerbation From CAP
• Distinguishing COPD and CAP in a patient
with a known history of COPD can be
challenging.
• If a chest x ray does not show evidence of
a new infiltrate, he/she is more likely to
have a COPD exacerbation.
69
• Although not all patients with a COPD exacerbation need
antibiotics, patients requiring hospitalization for COPD are
likely to have a moderate to severe COPD exacerbation for
which antibiotic therapy is recommended.
• Antibiotics do not improve outcomes in patients with asthma
exacerbations and should not be given unless there is also
evidence of concomitant CAP.

The Four Moments of Antibiotic Decision
Making
1. Does my patient have an infection that
requires antibiotics?
2. Have I ordered appropriate cultures before
starting antibiotics? What empiric therapy
should I initiate?
3. A day or more has passed. Can I stop
antibiotics? Can I narrow therapy or change
from IV to oral therapy?
4. What duration of antibiotic therapy is needed
for my patient's diagnosis?
70

Moments 2–4: Management of COPD
Exacerbations
• Common bacteria associated with COPD exacerbations include H.
influenzae and S. pneumoniae
• Sputum Gram stain and culture are not needed in many cases of
COPD exacerbation, but can be considered for patients with extensive
prior antibiotic exposure or a severe COPD exacerbation
• Most patients can be treated with 3 days of azithromycin11,12
• If a patient is already taking azithromycin, consider doxycycline,
amoxicillin/clavulanate, or cefuroxime for a 5-day course11,12
• Avoid use of fluoroquinolones unless prior or current microbiology
indicates infection with organisms resistant to standard therapy
71

: Prins HJ, Duijkers R, van der Valk P, et al. CRP-guided antibiotic
treatment in acute exacerbations of COPD in hospital admissions.
Eur Respir J 2019; 53: 1802014
72
Kaplan−Meier Curve for treatment failure over 30 days.
GOLD: Global Initiative for Chronic Obstructive Lung Disease; CRP:C-reactive
protein.

: Prins HJ, Duijkers R, van der Valk P, et al. CRP-guided antibiotic
treatment in acute exacerbations of COPD in hospital admissions.
Eur Respir J 2019; 53: 1802014
73

Fig 1. Distributions of the indices.
Su J, Liu Hy, Tan Xl, Ji Y, Jiang Yx, et al. (2015) Sputum Bacterial and Fungal Dynamics during Exacerbations of Severe COPD. PLOS ONE 10(7):
e0130736. https://doi.org/10.1371/journal.pone.0130736
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130736

Fig 3. Comparison of the bacterial communities at the phylum level and of representative genera with highly
abundant OTUs.
Su J, Liu Hy, Tan Xl, Ji Y, Jiang Yx, et al. (2015) Sputum Bacterial and Fungal Dynamics during Exacerbations of Severe COPD. PLOS ONE 10(7):
e0130736. https://doi.org/10.1371/journal.pone.0130736
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130736

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