systemic biomarkers in exacerbations of copd: the evolving ... ex.pdf · of copd: the evolving...

DOI 10.1378/chest.11-0495; Prepublished online August 11, 2011;Chest

Angela Koutsokera, Daiana Stolz, Stelios Loukides and Konstantinos Kostikas CHALLENGEOF COPD: THE EVOLVING CLINICAL SYSTEMIC BIOMARKERS IN EXACERBATIONS

http://chestjournal.chestpubs.org/content/early/2011/08/10/chest.11-0495

can be found online on the World Wide Web at: The online version of this article, along with updated information and services

) ISSN:0012-3692http://chestjournal.chestpubs.org/site/misc/reprints.xhtml(without the prior written permission of the copyright holder.reserved. No part of this article or PDF may be reproduced or distributedChest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights

ofbeen published monthly since 1935. Copyright2011by the American College is the official journal of the American College of Chest Physicians. It hasChest

Department at (847) 498-1400 or [email protected]. appear online. For inquriires, please contact the AACP Media Relations

Papers in Press are not under media or public embargo once theCHEST (DOI) and date of in-press publication. references to an in-press article must include the digital object identifiernonsubstantive changes. These articles are indexed by PubMed, but any edited or typeset. The final version may contain substantive ornot yet been published in an issue of the journal and have not yet been

Papers in Press are peer-reviewed, accepted articles that haveCHEST

Copyright © 2011 American College of Chest Physicians by Stylianos Loukides on November 14, 2011chestjournal.chestpubs.orgDownloaded from

1

Word Count: 3,666

Abstract Word Count: 248

SYSTEMIC BIOMARKERS IN EXACERBATIONS OF COPD: THE

EVOLVING CLINICAL CHALLENGE

Angela Koutsokera, MD1, [email protected]

Daiana Stolz, MD, FCCP2, [email protected]

Stelios Loukides, MD, FCCP3, [email protected]

Konstantinos Kostikas, MD, FCCP3, [email protected]

From the 1Service de Pneumologie et Rehabilitation Respiratoire, Hôpital de Rolle,

Switzerland; 2Clinic for Pulmonary Medicine and Respiratory Cell Research,

University Hospital Basel, Switzerland; 32

nd Respiratory Medicine Department,

University of Athens Medical School, Athens, Greece

Correspondence to:

Dr. Konstantinos Kostikas

Stamouli 3, Karditsa 43100, Greece

Tel + 30-6944780616, Fax +30-2441022370, e-mail [email protected]

Short Title: Systemic Biomarkers in COPD Exacerbations

Conflict of Interest: Dr. Stolz has received speakers’ honoraria from BRAHMS AG

(the manufacturer of pro-adrenomedullin, copeptin, pro-endothelin, and procalcitonin

assays) and was sponsored by BRAHMS AG for speaking engagements and research

(unrestricted grant). None of the other authors has any conflict of interest related to

the present manuscript.

Page 1 of 58


2

ABSTRACT

Word Count: 248

Background: Exacerbations of chronic obstructive pulmonary disease (ECOPD)

remain a major cause of mortality and morbidity of COPD patients. Despite advances

in the understanding of their pathophysiology, their assessment relies primarily on

clinical presentation which can be variable and difficult to predict. A large number of

biomarkers have already been assessed in this context and some appear to be

promising.

Methods: An online search for articles published until December 2010 was conducted

using 3 terms for ECOPD, 5 terms for biomarkers and 5 terms regarding the sampling

method. Biomarkers were evaluated for their potential role in the establishment and/or

confirmation of the diagnosis of ECOPD, the evaluation of etiology and severity, the

prediction of prognosis and the guidance of treatment decisions.

Results: Several systemic biomarkers have been measured in the context of ECOPD

and most of them have been found to increase at ECOPD onset and to subside during

the course of exacerbations. Correlations have been reported among these biomarkers

but direct associations with clinical variables have been more difficult to establish.

Although there are several limitations yet to be addressed, some of the biomarkers,

and most notably C-reactive protein for the identification of a COPD exacerbation and

procalcitonin for antibiotic guidance, may provide clinically relevant information.

Conclusions: So far no single biomarker has been able to gain wide acceptance, but

some provide clinically useful information. The evaluation of such biomarkers in

large decision-making studies is expected to become an area of intense investigation

in the near future.

Page 2 of 58


3

KEYWORDS

COPD

Exacerbation

Biomarkers

Antibiotics

Page 3 of 58


4

ABBREVIATIONS

ATS/ERS: American Thoracic Society / European Respiratory Society

AUC: area under the curve

BNP: brain natriuretic peptide

COPD: chronic obstructive pulmonary disease

CRP: C-reactive protein

ECOPD: exacerbations of COPD

ECP: eosinophil cationic protein

HRV: human rhinovirus

ICU: intensive care unit

IL-6: interleukin 6

IP-10: IFN-γ induced protein 10

MMP-9: matrix metalloproteinase 9

MPIF-1: myeloid progenitor inhibitory factor-1

NIV: non invasive ventilation

PCT: procalcitonin

ProADM: pro-adrenomedullin

ProET1: proendothelin 1

SAA: serum amyloid A

sIL-5Rα: soluble interleukin 5 receptor α

sTNFR: soluble tumor necrosis factor receptor

sTREM-1: Soluble form of the triggering receptor expressed on myeloid cells

TEAC: Trolox equivalent antioxidant capacity

TNF-α: tumor necrosis factor α

Page 4 of 58


5

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) patients are susceptible to periodic

deteriorations of their illness that are mainly triggered by bacterial and viral

pathogens, called exacerbations of COPD (ECOPD). Frequent ECOPD accelerate

lung function decline and have major implications on the quality of life, morbidity

and mortality of COPD patients1. Currently ECOPD are diagnosed on clinical

grounds, when specific symptoms deteriorate beyond day-to-day variability, and their

severity is rated according to healthcare resource utilization1,2

. The identification of

ECOPD etiology often remains unclear and treatment decisions are usually empirical.

Biomarkers are biological molecules that can be used as indicators of normal

biologic processes, pathogenic processes or responses to therapeutic interventions.

While their use is not intended as a substitute for clinical judgment, biomarkers may

be valuable tools for describing the natural history of the disease as well as in helping

management, clinical decision making and predicting outcomes. Several systemic

biomarkers of inflammation and oxidative stress have been studied in ECOPD but

none has gained wide acceptance so far. The aim of this review is to provide an

overview of the systemic biomarkers studied in the context of ECOPD and to

highlight the most promising molecules, by dissecting their relative contribution to

clinical decision making and prediction of outcomes.

METHODOLOGY AND DEFINITIONS

A search for articles published in the English language until December 2010 was

conducted using Medline and Highwire databases as well as the reference lists of

reviews and retrieved articles. We combined 3 terms for ECOPD (COPD

exacerbation, COPD deterioration, acute COPD) with 5 terms related to biomarkers

Page 5 of 58


6

(biomarkers, acute phase proteins, cytokines, oxidative stress) and 5 terms regarding

the sampling method (serum, plasma, systemic, circulating levels, peripheral blood).

Abstracts or unpublished reports were not included in this review. Data obtained from

mixed populations (e.g. subjects with lower respiratory tract infection, patients with

respiratory failure or exacerbations of obstructive pulmonary disease in general) were

not included in the analysis. The methodology used was in accordance with the

suggestions of the MOOSE guidelines3. Figure 1 provides a flow chart diagram of

search strategy and study selection.

The current literature is characterized by an evident lack of consensus regarding

the definition of baseline, ECOPD onset and disease stability as well as by a vast

heterogeneity in study designs. The diversity of accumulating evidence renders result

interpretation difficult. In order to resolve the observed discrepancies of extracted

data, the following terminology was applied invariably in the current review:

• The term baseline describes a time point before the development of ECOPD,

i.e. during a phase of clinical stability, and this term has been used only for

longitudinal studies (paired samples).

• The term ECOPD onset has been used to describe the first time-point that the

patients suffering from an exacerbation were assessed by the investigators.

• The terms stability or recovery after an exacerbation were avoided and we have

used instead the specific time point of the measurement, e.g. Day 35 or Month

1.

• Finally, the term stable COPD was used only for cross-sectional studies that

compared ECOPD patients with another group of stable COPD patients (not

referring to paired samples).

Page 6 of 58


7

SYSTEMIC BIOMARKERS AND THE NATURAL HISTORY OF ECOPD

Several studies have measured numerous systemic biomarkers at ECOPD onset or

during recovery. Although not invariably demonstrated, most of the studied

inflammatory biomarkers increase at ECOPD onset and subside during the course of

exacerbations. This is especially true for C-reactive protein (CRP), the most widely

studied molecule in literature to-date, as well as for other acute phase proteins and

pro-inflammatory biomarkers. The presence of an anti-oxidant imbalance is also

considered to play an important role during the course of an ECOPD4-6

. These events

are associated with modifications of the levels of other metabolically active

molecules, such as copeptin7, leptin

8 or erythropoietin

9, as well as with modifications

of molecules expressed on circulating cells10,11

. The Tables A to D of the online

supplement provide a detailed overview of the biomarkers measured in ECOPD,

whereas Tables 1 and 2 specifically focus on the major finding concerning CRP and

procalcitonin (PCT). Although many of these biomarkers correlate with each other,

direct associations with clinically important variables have been more difficult to

establish (Table C of the online supplement).

The ultimate goal for clinicians is to draw clinically relevant conclusions from

research data in order to improve patient outcomes. This can be a very challenging

task as there is currently a large pool of candidate biomarkers studied in ECOPD. In

the following paragraphs we will focus on the clinical relevance of these biomarkers,

by discussing their potential role in the establishment and/or confirmation of the

diagnosis, the evaluation of etiology and severity, the prediction of prognosis and the

guidance of treatment decisions. Table 3 summarizes the biomarkers that have been

assessed in these directions.

Page 7 of 58


8

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF ECOPD

Currently, and in the absence of specific biomarkers, ECOPD are diagnosed on

clinical grounds2. Biomarkers contributing to a prompt diagnosis of an imminent or

established ECOPD may modify treatment decisions and patient outcomes. In the

largest study to-date, Hurst et al. investigated the ability of 36 biomarkers to identify

ECOPD, and suggested that the three best performing molecules were CRP,

interleukin 6 (IL-6) and myeloid progenitor inhibitory factor-1 (MPIF-1)12

. The most

selective biomarker was CRP, presenting a moderate diagnostic performance with an

area under the curve (AUC) of 0.73, that provided 40% sensitivity and a 90%

specificity for a cut-off point of 27.6 mg/l12

. None of those biomarkers in isolation

could provide a better diagnostic performance compared to the presence of any major

ECOPD symptoms (dyspnea, sputum volume, or sputum purulence). The best

combination of three biomarkers [CRP, matrix metalloproteinase 9 (MMP-9), and

MPIF-1] resulted in an AUC which was not significantly better than CRP alone12

, but

the addition of CRP to any major symptom significantly increased the AUC to 0.88.

Several other studies have supported a possible role for CRP in the identification of an

ECOPD, however with modest diagnostic accuracy.

Data on the use of biomarkers for the differential diagnosis of ECOPD are

limited. In patients with mild exacerbation of bronchospastic symptoms, the values of

IL-1ra, IL-4 and IL-6 were lower in asthma than in ECOPD13

. In another study

involving 150 patients with acute respiratory infections, patients with pneumonia

presented the highest levels of the soluble form of the triggering receptor expressed on

myeloid cells-1 (sTREM-1), followed by ECOPD, asthma exacerbations and

controls14

. In a recent retrospective study of 319 patients hospitalized for pneumonia,

asthma exacerbation or ECOPD, CRP values greater than 48mg/L providing a

Page 8 of 58


9

sensitivity of 91% and a specificity of 93% for identifying patients with pneumonia15

.

However, prospective studies are needed for the evaluation of these biomarkers in the

differential diagnosis of ECOPD from other conditions with similar clinical

presentation.

ETIOLOGY OF ECOPD

ECOPD can be precipitated by pollutants, bacterial and viral causes, but in the

majority of cases the exact cause is not recognized. The identification of biomarkers

that may help in the identification of ECOPD etiology has possible treatment

implications. CRP has been invariably associated with increased sputum purulence16-

19, but studies that provide a bacteriological analysis do not reach common

conclusions, as some investigators describe increased CRP levels in bacterial

ECOPD20,21

and others don’t22,23

. Bircan et al. reported that a CRP cut-off point of

more than 10mg/l has 84% sensitivity but with 38.4% specificity for detecting

bacterial infections24

. When analyzed as the percentage change from stable state to

ECOPD, CRP shows a significantly larger increase in bacterial exacerbations25

,

whereas a study showed that the odds of a bacterial ECOPD increases by 57% per 1-

unit increase in logeCRP22

. Interestingly, the predictive value of CRP to distinguish an

ECOPD due to a new bacterial strain improves when it is combined with sputum

tumor necrosis factor α (TNF-α) and sputum neutrophil elastase26

. In the same

context, IL-625

and serum amyloid A (SAA)22

levels have been found significantly

elevated in bacterial ECOPD, whereas glucose23

, insulin23

, leptin23

, brain natriuretic

peptide (BNP)27

, PCT21,28

, pro-adrenomedullin (ProADM)29

, proendothelin 1 (ProET-

1)29

and soluble tumor necrosis factor receptors R55 and R7523

(sTNF-R55,

Page 9 of 58


10

sTNF/R75) failed to differentiate between patients with positive and negative sputum

cultures for bacteria.

Viral ECOPD have been associated with increased eosinophil cationic protein

(ECP)30

, soluble interleukin 5 receptor α (sIL5Rα)30

, fibrinogen31

and interferon-γ

induced protein 10 (IP-10)32

. Fibrinogen levels were elevated in viral ECOPD31

,

whereas Quint et al. have shown that IP-10 was increased in human rhinovirus

(HRV)-positive ECOPD, presenting a significant correlation to viral load32

.

According to this study, a cut-off point of 260pg/ml of IP-10 in the presence of cold

symptoms would be 80% specific and 67% sensitive for a HRV ECOPD32

. On the

other hand, CRP32,33

and PCT28,33

could not discriminate virus-associated ECOPD

from others, whereas the role of IL-6 has not yet been elucidated. Seemungal et al.

showed that serum IL-6 were higher in viral than in non-viral ECOPD, with the

difference not reaching statistical significance31

. Although one study showed that

ECOPD with both rhinovirus and Haemophilus influenza are associated with higher

serum IL-6 than ECOPD without both pathogens34

, other studies have shown that IL-

6 is not associated with either the detection of respiratory syncytial virus31

or the viral

load in sputum32

.

EVALUATION OF ECOPD SEVERITY

Stratification of ECOPD severity is usually made with the use of the ATS/ERS

criteria, focusing on health care resource utilization1,2

or with Anthonisen’s criteria

which stratify patients according to the presence of symptoms and sputum

purulence35

. Both classifications are based on the subjective evaluation of clinical

presentation and biomarkers are needed for a more objective evaluation of severity.

Page 10 of 58


11

Patients with severe ECOPD requiring admission to the intensive care unit

(ICU) present higher levels of BNP27

, copeptin36

, ProADM29

and PCT36

on admission.

In the same context, peak levels of troponin have been associated with the need for

noninvasive ventilation37

. On the other hand, CRP36

and ProET-129

levels did not

differ between patients admitted to the ICU and those receiving ward care.

CRP levels were significantly higher in patients with Anthonisen’s type I

ECOPD36

and correlated with the clinical severity assessed by a clinical score26

.

However, no difference was found in CRP between ATS/ERS level I and II/III

ECOPD and this biomarker performed no better than dyspnea or Anthonisen's criteria

in predicting severe episodes36

. When using the ratio of ECOPD onset to stable state

value to predict severe episodes, a cutoff point of a twofold change of CRP was 80%

sensitive and 54% specific with a positive and a negative likelihood ratio of 1.73 and

0.37 respectively22

.

SAA, another acute phase protein, was significantly elevated in ERS/ATS

level II/III events versus level I ECOPD and a fourfold or greater increase above basal

levels was associated with a severe ECOPD. Specifically, at a cut-off of 12.5 mg/L,

SAA had a 87% sensitivity for severe ECOPD with a negative predictive value of

92%. In contrast to CRP, SAA was better than dyspnea or Anthonisen’s criteria in

predicting severe episodes, whereas the combination of CRP or SAA with a major

symptom did not improve the prediction of a severe ECOPD over SAA alone22

.

Regarding other biomarkers, sTREM-1 levels were higher in Anthonisen type

1 ECOPD14

, whereas PCT maximal levels (assessed with 3 samplings within the first

24 hours of admission) of more than 0.25µg/l were present in more critically ill

patients28

. In the case of PCT a cut-off of point of 12.5µg/l had 54% sensitivity and

79% negative predictive value for severe ECOPD22

. On the contrary, BNP27

,

Page 11 of 58


12

ProADM29

or ProET-129

could not discriminate ECOPD type according to

Anthonisen’s criteria, whereas the study of Hurst et al. found no statistically

significant role in the evaluation of ECOPD severity for its 36 investigated

biomarkers12

.

GUIDANCE OF ANTIBIOTIC USE

Only a subgroup of patients suffering from ECOPD benefit from a treatment with

antibiotics, and biomarkers that can aid in the identification of such subjects may help

in limiting antibiotic use and microbiological resistance. PCT has been studied the

most for its potential to define the need for antibiotic use in patients with ECOPD.

The study of Stolz et al. discouraged the use of antibiotics for procalcitonin levels

<0.1 µg/L and recommended their administration for levels >0.25 µg/L, whereas for

levels between 0.1-0.25 µg/L antibiotic use was based on clinical judgment38

. This

study showed that procalcitonin guidance offered a sustained advantage over standard

therapy in reducing antibiotic use for up to 6 months with a number-needed-to treat of

3, whereas clinical outcomes, including exacerbation rate and time to next

exacerbation, were not compromised38

. These results were in line with studies

focusing on populations with lower respiratory tract infections that assessed ECOPD

patients in subgroup analyses (even if procalcitonin cut-off points and

recommendations are not common between those studies)39,40

.

In contrast, the study of Daniels et al. suggested that PCT levels did not differ

in the presence or absence of bacteria and patients with low PCT levels did benefit

from antibiotics21

. In this study data were obtained from a randomized placebo

controlled trial on doxycycline in addition to systemic corticosteroids for ECOPD and

treatment success was defined as a complete resolution or reduction of the symptoms

Page 12 of 58


13

and signs in the absence of the occurrence of a new infection. The discrepancy of the

results was attributed to different study designs, especially as far as population

characteristics and studied outcomes were concerned. Moreover, in the study by Stolz

et al. patients were randomized to either management based on PCT values or

standard care, further supporting a possible role for PCT. It is also worth mentioning,

that in the study by Daniels et al. most patients with low PCT levels had a high CRP.

Although clinicians had knowledge of the CRP values and this might have influenced

treatment decisions, a gradually increasing treatment effect of doxycycline was

observed for increasing levels of CRP21

.

CLINICAL EVOLUTION OF ECOPD

(a) Duration of hospitalization

A positive correlation with the length of hospital stay has been described for

copeptin36

, ProADM29

, ProET129

, albumin41

, troponin37,42

, BNP27

levels and for

ECOPD associated with eosinopenia43

. Interestingly, copeptin levels less than

40pmol/l on admission were associated with a mean length of hospital stay of 9 days

as compared to 14 days in subjects with more than 40pmol/l36

. In the case of troponin,

patients with raised levels had longer hospitalizations42

, but only peak levels could

predict the length of hospitalization37

. A trend for a shorter duration of hospitalization

was also observed in patients with low procalcitonin levels, but this difference did not

reach statistical significance36

. In ICU patients, BNP27

and copeptin36

levels on

admission correlated with the length of ICU stay, whereas no significant correlations

were reported for PCT28,36

, ProADM29

, CRP36

or ProET-129

.

(b) Duration of symptomatic recovery and development of complications

Page 13 of 58


14

Only a few papers have focused on the subject and most studies investigated the

predictive role of CRP on the duration of symptomatic recovery. One study described

similar CRP levels on admission between the subgroup of patients who subsequently

reported persistent symptoms by Day 10 as compared to those who reported symptom

resolution6. In another study, patients who had not recovered from ECOPD by day 35

had persistently higher serum CRP levels during the recovery period44

. Several other

biomarkers such as fibrinogen6, TNF-α

6, SAA

6 and IL-6

6,44 were not related to

symptom recovery time.

Regarding the development of complications, data on CRP are contradictory,

as some investigators report no correlation with long term clinical failure36

, whereas

others have showed that overall complications are correlated with CRP levels on

admission and with peak CRP levels37

. In the area of investigation, copeptin appears

to be a promising biomarker, as its levels on admission were associated with long

term clinical failure, especially when they were combined with a history of ECOPD

hospitalization during the previous year36

. This was not demonstrated for PCT36

.

(c) ECOPD frequency and recurrence

Several biomarkers have been assessed as indicators of an impending ECOPD. Some

have been measured during clinical stability and have been associated with the

frequency of exacerbations or the incidence of hospitalization of COPD patients

(Table 4). However only a limited number of studies focused on biomarkers sampled

at or after the onset of an exacerbation on ECOPD and attempted to predict ECOPD

frequency or recurrence. Perera et al. showed a significantly different evolution of

serum IL-6 and CRP between frequent and infrequent exacerbators44

. More

specifically, a higher concentration of CRP 14 days after the onset of an exacerbation

Page 14 of 58


15

was associated with a shorter time to the next ECOPD, whereas elevated CRP levels

at Day 14 were related to ECOPD recurrence within 50 days, independent of disease

severity, ECOPD frequency or treatment with oral steroids44

. On the other hand, PCT

had no predictive value on ECOPD recurrence28

and albumin levels did not differ in

patients readmitted with ECOPD41

.

(d) Prediction of mortality

ProADM has been shown to be independently associated with 2 year survival, as

higher admission levels were found in hospital non-survivors and in long-term non-

survivors29

. The best diagnostic cut-off value was 0.77 nmol/l with a sensitivity of

0.81 and a specificity of 0.53 to predict death at two years. Moreover, as compared to

patients with proADM levels <0.84 nmol/l, the odds ratio for mortality within 2 years

in patients presenting with proADM ≥0.84 nmol/l at hospital admission was 3.12

(95% confidence interval 1.35 to 7.58)29

.

ProET-1, copeptin and PCT have also been studied in this context. ProET-1

levels did not differ in those who survived and deceased during hospitalization but

higher admission levels were observed in long-term non-survivors29

. Copeptin tended

to be higher in non-survivors as far as in hospital mortality was concerned with an

area under the curve for survival at 0.75 (higher than CRP and similar to PCT). A cut-

off point of 53 pmol/l had a sensitivity of 58% and a specificity of 80% to predict

mortality until follow-up and this biomarker was found to be an independent predictor

of outcome7. PCT was also associated with 2 year mortality with a hazard ratio of

1.517(95% CI, 1.144-2.010)29

, whereas PCT levels at admission of more than

0.25µg/l were associated with ICU mortality28

.

Page 15 of 58


16

CRP7,29,36,45

and BNP27

failed to predict mortality, whereas data concerning the

prognostic value of troponin on hospital mortality are contradictory, with some

investigators describing no difference37,42

and others reporting elevated levels as a

strong predictor of in-hospital death46

. However, most of the studies conclude that

elevated troponin during ECOPD is associated with increased risk of death after

discharge45

.

Finally, a retrospective study, reported that eosinopenia was associated with

increased mortality independent of age, white blood count and blood pH. Although

prospective studies are lacking, this observation is rather interesting as it might be

associated with the airway eosinophilia observed in some cases of ECOPD43,47

.

PROMISING BIOMARKERS AND FUTURE CHALLENGES

The evolution of a candidate biomarker to a clinical assay should conceptually

involve the following steps: (1) demonstrated association with the diagnosis or

outcome of interest; (2) prospective validation in independent cohorts of patients

representative of the intended target populations; (3) documentation of significant

incremental information when added to existing clinical information; (4) assessment

of effects on patient management and outcomes; and (5) cost effectiveness. It is

noteworthy that in this long pathway of biomarker validation, statistical factors are

not the only parameter to consider, as availability, ease of interpretation and cost play

also a major role48,49

. Although, most of the candidate biomarkers or their

combinations have not gone beyond the first steps of this pathway current literature is

rapidly evolving. Despite of the several limitations that hamper wide application and

acceptance, clinically useful information can be extracted for the biomarkers that have

been studied the most. For example, CRP has a modest diagnostic performance in the

Page 16 of 58


17

identification of ECOPD (40% sensitivity and a 90% specificity for a cut-off point of

27.6 mg/l) which does not transcend the diagnostic performance of any major ECOPD

symptom but it has been demonstrated that the addition of CRP to any major

symptom increases significantly the diagnostic performance of the latter12

. Moreover,

when analyzed as the percentage change from stable state to ECOPD, CRP shows a

significantly larger increase in bacterial exacerbations22,25

and may predict severe

episodes, although it does not perform better than dyspnea or Anthonisen’s

criteria25,36

. PCT has also been associated with the severity stratification of ECOPD

and it has been shown that PCT-guided treatment leads to a reduction of antibiotic use

without compromising clinical outcomes38

. Finally, SAA could also be a promising

marker, as a fourfold increase above basal levels was associated with severe ECOPD

episodes, performing better than dyspnea or Anthonisen’s criteria in predicting

severity22

.

For the immediate future, the combination of multiple, complementary and

independent, biomarkers measured in the same or different samples holds great

promise and is apt to become an area of intense investigation. Moreover,

combinations of systemic and local biomarkers could provide useful information.

Additionally, genomics and more specifically proteomics, a method of studying the

entire protein complement of the genome, are in the frontier of medical research. This

technique has the potential to provide an insight in the various interactions among

different pathways, but in the absence of a thoughtful approach it runs the risk of

merely increasing complexity without significantly improving clinical

outcomes48,50,51

. Statistical methods, such as the decision curve analysis, are

increasingly implemented in this context in order to improve the clinical relevance of

the statistical analysis52

.

Page 17 of 58


18

CONCLUSIONS

In this review we summarized the majority of studies that evaluated candidate

systemic biomarkers for the diagnosis and classification of ECOPD, the facilitation of

management decisions and the prognosis of COPD patients on exacerbation. Despite

the promising results of many studies, the contradictory findings suggest that no

single biomarker is likely to accomplish all the above targets. Taking into

consideration the several limitations yet to be addressed, some of the biomarkers, and

most notably CRP for the identification of a COPD exacerbation and PCT for

antibiotic guidance, may provide clinically relevant information. Therefore, the way

ahead possibly leads through the validation of existing biomarkers in large clinical

trials, the combination of biomarkers with important clinical information in decision-

making studies and the evolution of novel disease-specific systemic biomarkers.

ACKNOWLEDGEMENTS

KK and SL were involved in the conception of the present review. AK, DS, and KK

prepared the manuscript. KK and SL were involved in revising the manuscript for

important intellectual content. All authors read and approved the final manuscript.

Page 18 of 58


19

REFERENCES

1. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients

with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932-

46.

2. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis,

management, and prevention of chronic obstructive pulmonary disease: GOLD

executive summary. Am J Respir Crit Care Med 2007;176:532-55.

3. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies

in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in

Epidemiology (MOOSE) group. Jama 2000;283:2008-12.

4. Rahman I, Skwarska E, MacNee W. Attenuation of oxidant/antioxidant

imbalance during treatment of exacerbations of chronic obstructive pulmonary

disease. Thorax 1997;52:565-8.

5. Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in

asthma, COPD, and smokers. Am J Respir Crit Care Med 1996;154:1055-60.

6. Koutsokera A, Kiropoulos TS, Nikoulis DJ, et al. Clinical, functional and

biochemical changes during recovery from COPD exacerbations. Respir Med

2009;103:919-26.

7. Muller B, Morgenthaler N, Stolz D, et al. Circulating levels of copeptin, a

novel biomarker, in lower respiratory tract infections. Eur J Clin Invest 2007;37:145-

52.

8. Kythreotis P, Kokkini A, Avgeropoulou S, et al. Plasma leptin and insulin-like

growth factor I levels during acute exacerbations of chronic obstructive pulmonary

disease. BMC Pulm Med 2009;9:11.

Page 19 of 58


20

9. Sala E, Balaguer C, Villena C, et al. Low Erythropoietin Plasma Levels during

Exacerbations of COPD. Respiration 2010;80:190-7.

10. Noguera A, Busquets X, Sauleda J, Villaverde JM, MacNee W, Agusti AG.

Expression of adhesion molecules and G proteins in circulating neutrophils in chronic

obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:1664-8.

11. Tkacova R, Kluchova Z, Joppa P, Petrasova D, Molcanyiova A. Systemic

inflammation and systemic oxidative stress in patients with acute exacerbations of

COPD. Respir Med 2007;101:1670-6.

12. Hurst JR, Donaldson GC, Perera WR, et al. Use of plasma biomarkers at

exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med

2006;174:867-74.

13. Stankiewicz W, Dabrowski MP, Chcialowski A, Plusa T. Cellular and

cytokine immunoregulation in patients with chronic obstructive pulmonary disease

and bronchial asthma. Mediators Inflamm 2002;11:307-12.

14. Phua J, Koay ES, Zhang D, et al. Soluble triggering receptor expressed on

myeloid cells-1 in acute respiratory infections. Eur Respir J 2006;28:695-702.

15. Bafadhel M, Clark TW, Reid C, et al. Procalcitonin and C reactive protein in

hospitalised adult patients with community acquired pneumonia, exacerbation of

asthma and chronic obstructive pulmonary disease. Chest 2010 Oct 28. [Epub ahead

of print].

16. Gompertz S, O'Brien C, Bayley DL, Hill SL, Stockley RA. Changes in

bronchial inflammation during acute exacerbations of chronic bronchitis. Eur Respir J

2001;17:1112-9.

Page 20 of 58


21

17. Stockley RA, O'Brien C, Pye A, Hill SL. Relationship of sputum color to

nature and outpatient management of acute exacerbations of COPD. Chest

2000;117:1638-45.

18. Weis N, Almdal T. C-reactive protein--can it be used as a marker of infection

in patients with exacerbation of chronic obstructive pulmonary disease? Eur J Intern

Med 2006;17:88-91.

19. Brusse-Keizer MG, Grotenhuis AJ, Kerstjens HA, et al. Relation of sputum

colour to bacterial load in acute exacerbations of COPD. Respir Med 2009;103:601-6.

20. Dev D, Wallace E, Sankaran R, et al. Value of C-reactive protein

measurements in exacerbations of chronic obstructive pulmonary disease. Respir Med

1998;92:664-7.

21. Daniels JM, Schoorl M, Snijders D, et al. Procalcitonin vs C-reactive protein

as predictive markers of response to antibiotic therapy in acute exacerbations of

COPD. Chest 2010;138:1108-15.

22. Bozinovski S, Hutchinson A, Thompson M, et al. Serum amyloid a is a

biomarker of acute exacerbations of chronic obstructive pulmonary disease. Am J

Respir Crit Care Med 2008;177:269-78.

23. Creutzberg EC, Wouters EF, Vanderhoven-Augustin IM, Dentener MA,

Schols AM. Disturbances in leptin metabolism are related to energy imbalance during

acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care

Med 2000;162:1239-45.

24. Bircan A, Gokirmak M, Kilic O, Ozturk O, Akkaya A. C-reactive protein

levels in patients with chronic obstructive pulmonary disease: role of infection. Med

Princ Pract 2008;17:202-8.

Page 21 of 58


22

25. Bathoorn E, Liesker JJ, Postma DS, et al. Change in inflammation in out-

patient COPD patients from stable phase to a subsequent exacerbation. Int J Chron

Obstruct Pulmon Dis 2009;4:101-9.

26. Sethi S, Wrona C, Eschberger K, Lobbins P, Cai X, Murphy TF. Inflammatory

profile of new bacterial strain exacerbations of chronic obstructive pulmonary disease.

Am J Respir Crit Care Med 2008;177:491-7.

27. Stolz D, Breidthardt T, Christ-Crain M, et al. Use of B-Type Natriuretic

Peptide in the Risk Stratification of Acute Exacerbations of COPD. Chest

2008;133:1088-94.

28. Daubin C, Parienti JJ, Vabret A, et al. Procalcitonin levels in acute

exacerbation of COPD admitted in ICU: a prospective cohort study. BMC Infect Dis

2008;8:145.

29. Stolz D, Christ-Crain M, Morgenthaler NG, et al. Plasma pro-adrenomedullin

but not plasma pro-endothelin predicts survival in exacerbations of COPD. Chest

2008;134:263-72.

30. Rohde G, Gevaert P, Holtappels G, et al. Soluble interleukin-5 receptor alpha

is increased in acute exacerbation of chronic obstructive pulmonary disease. Int Arch

Allergy Immunol 2004;135:54-61.

31. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses,

symptoms, and inflammatory markers in acute exacerbations and stable chronic


32. Quint JK, Donaldson GC, Goldring JJ, Baghai-Ravary R, Hurst JR, Wedzicha

JA. Serum IP-10 as a biomarker of human rhinovirus infection at exacerbation of

COPD. Chest 2010;137:812-22.

Page 22 of 58


23

33. Kherad O, Kaiser L, Bridevaux PO, et al. Upper viral respiratory infection,

biomarkers and chronic obstructive pulmonary disease (COPD) exacerbations. Chest

2010;138:896-904.

34. Wilkinson TM, Hurst JR, Perera WR, Wilks M, Donaldson GC, Wedzicha JA.

Effect of interactions between lower airway bacterial and rhinoviral infection in

exacerbations of COPD. Chest 2006;129:317-24.

35. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson

NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease.

Ann Intern Med 1987;106:196-204.

36. Stolz D, Christ-Crain M, Morgenthaler NG, et al. Copeptin, C-reactive

protein, and procalcitonin as prognostic biomarkers in acute exacerbation of COPD.

Chest 2007;131:1058-67.

37. Martins CS, Rodrigues MJ, Miranda VP, Nunes JP. Prognostic value of

cardiac troponin I in patients with COPD acute exacerbation. Neth J Med

2009;67:341-9.

38. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of

exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-

guidance with standard therapy. Chest 2007;131:9-19.

39. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitonin-

guided treatment on antibiotic use and outcome in lower respiratory tract infections:

cluster-randomised, single-blinded intervention trial. Lancet 2004;363:600-7.

40. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based

guidelines vs standard guidelines on antibiotic use in lower respiratory tract

infections: the ProHOSP randomized controlled trial. Jama 2009;302:1059-66.

Page 23 of 58


24

41. Giron R, Matesanz C, Garcia-Rio F, et al. Nutritional state during COPD

exacerbation: clinical and prognostic implications. Ann Nutr Metab 2009;54:52-8.

42. Harvey MG, Hancox RJ. Elevation of cardiac troponins in exacerbation of

chronic obstructive pulmonary disease. Emerg Med Australas 2004;16:212-5.

43. Holland M, Alkhalil M, Chandromouli S, Janjua A, Babores M. Eosinopenia

as a marker of mortality and length of stay in patients admitted with exacerbations of

chronic obstructive pulmonary disease. Respirology 2010;15:165-7.

44. Perera WR, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery

and recurrence at COPD exacerbation. Eur Respir J 2007;29:527-34.

45. Brekke PH, Omland T, Holmedal SH, Smith P, Soyseth V. Troponin T

elevation and long-term mortality after chronic obstructive pulmonary disease

exacerbation. Eur Respir J 2008;31:563-70.

46. Baillard C, Boussarsar M, Fosse JP, et al. Cardiac troponin I in patients with

severe exacerbation of chronic obstructive pulmonary disease. Intensive Care Med

2003;29:584-9.

47. Saetta M, Di Stefano A, Maestrelli P, et al. Airway eosinophilia in chronic

bronchitis during exacerbations. Am J Respir Crit Care Med 1994;150:1646-52.

48. Allen LA. Use of multiple biomarkers in heart failure. Curr Cardiol Rep

2010;12:230-6.

49. Shariat SF, Lotan Y, Vickers A, et al. Statistical consideration for clinical

biomarker research in bladder cancer. Urol Oncol;28:389-400.

50. Bowler RP, Ellison MC, Reisdorph N. Proteomics in pulmonary medicine.

Chest 2006;130:567-74.

Page 24 of 58


25

51. Hirsch J, Hansen KC, Burlingame AL, Matthay MA. Proteomics: current

techniques and potential applications to lung disease. Am J Physiol Lung Cell Mol

Physiol 2004;287:L1-23.

52. Vickers AJ, Cronin AM, Elkin EB, Gonen M. Extensions to decision curve

analysis, a novel method for evaluating diagnostic tests, prediction models and

molecular markers. BMC Med Inform Decis Mak 2008;8:53.

53. Crooks SW, Bayley DL, Hill SL, Stockley RA. Bronchial inflammation in

acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur

Respir J 2000;15:274-80.

54. Dentener MA, Creutzberg EC, Schols AM, et al. Systemic anti-inflammatory

mediators in COPD: increase in soluble interleukin 1 receptor II during treatment of

exacerbations. Thorax 2001;56:721-6.

55. Hill AT, Campbell EJ, Bayley DL, Hill SL, Stockley RA. Evidence for

excessive bronchial inflammation during an acute exacerbation of chronic obstructive

pulmonary disease in patients with alpha(1)-antitrypsin deficiency (PiZ). Am J Respir

Crit Care Med 1999;160:1968-75.

56. Hurst JR, Perera WR, Wilkinson TM, Donaldson GC, Wedzicha JA. Systemic

and upper and lower airway inflammation at exacerbation of chronic obstructive

pulmonary disease. Am J Respir Crit Care Med 2006;173:71-8.

57. Krommidas G, Kostikas K, Papatheodorou G, et al. Plasma leptin and

adiponectin in COPD exacerbations: Associations with inflammatory biomarkers.

Respir Med 2010;104:40-6.

58. Lazar Z, Huszar E, Kullmann T, et al. Adenosine triphosphate in exhaled

breath condensate of healthy subjects and patients with chronic obstructive pulmonary

disease. Inflamm Res 2008;57:367-73.

Page 25 of 58


26

59. Spruit MA, Gosselink R, Troosters T, et al. Muscle force during an acute

exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and

IGF-I. Thorax 2003;58:752-6.

60. Shakoori TA, Sin DD, Ghafoor F, Bashir S, Bokhari SN. Serum surfactant

protein D during acute exacerbations of chronic obstructive pulmonary disease. Dis

Markers 2009;27:287-94.

61. Daniels JM, Schoorl M, Snijders D, et al. Procalcitonin versus C-reactive

protein as predictive markers of response to antibiotic therapy in acute exacerbations

of COPD. Chest.

62. Wedzicha JA, Seemungal TA, MacCallum PK, et al. Acute exacerbations of

chronic obstructive pulmonary disease are accompanied by elevations of plasma

fibrinogen and serum IL-6 levels. Thromb Haemost 2000;84:210-5.

63. Chakrabarti B, Angus RM, Agarwal S, Lane S, Calverley PM.

Hyperglycaemia as a predictor of outcome during non-invasive ventilation in

decompensated COPD. Thorax 2009;64:857-62.

64. Engstrom G, Segelstorm N, Ekberg-Aronsson M, Nilsson PM, Lindgarde F,

Lofdahl CG. Plasma markers of inflammation and incidence of hospitalisations for

COPD: results from a population-based cohort study. Thorax 2009;64:211-5.

65. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard

BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary

disease. Am J Respir Crit Care Med 2007;175:250-5.

66. Gompertz S, Bayley DL, Hill SL, Stockley RA. Relationship between airway

inflammation and the frequency of exacerbations in patients with smoking related

COPD. Thorax 2001;56:36-41.

Page 26 of 58


27

67. Eagan TM, Ueland T, Wagner PD, et al. Systemic inflammatory markers in

COPD: results from the Bergen COPD Cohort Study. Eur Respir J;35:540-8.

68. Roland M, Bhowmik A, Sapsford RJ, et al. Sputum and plasma endothelin-1

levels in exacerbations of chronic obstructive pulmonary disease. Thorax 2001;56:30-

5.

69. Donaldson GC, Seemungal TA, Patel IS, et al. Airway and systemic

inflammation and decline in lung function in patients with COPD. Chest

2005;128:1995-2004.

70. Groenewegen KH, Postma DS, Hop WC, Wielders PL, Schlosser NJ, Wouters

EF. Increased systemic inflammation is a risk factor for COPD exacerbations. Chest

2008;133:350-7.

71. Eagan TM, Aukrust P, Bakke PS, et al. Systemic mannose-binding lectin is

not associated with Chronic Obstructive Pulmonary Disease. Respir Med;104:283-90.

72. Eagan TM, Damas JK, Ueland T, et al. Neutrophil Gelatinase Associated

Lipocalin - a biomarker in Chronic Obstructive Pulmonary Disease. Chest.

73. Lomas DA, Silverman EK, Edwards LD, et al. Serum surfactant protein D is

steroid sensitive and associated with exacerbations of COPD. Eur Respir J 2009.

Page 27 of 58


28

Table 1

Assessment of CRP at ECOPD onset (cross-sectional design) and during the course of

ECOPD (longitudinal design). An extended version of this Table is included in the

Online Supplement of this paper.

Reference Course: from

baseline to

ECOPD onset

Comparisons at ECOPD onset Course:

during

ECOPD

Bathoorn25

↔

Bircan24

ECOPD>controls, ECOPD>stable COPD,

ECOPD<pneumonia

Bozinovski22

↑ ECOPD>stable COPD ↓

↔: level I, level II/III ECOPD

bacterial>non-bacterial ECOPD

Brekke45

59% and 53% had ≥50mg/l

Creutzberg23

ECOPD>controls, ↔:With or without bacterial

infection

↓

Crooks53

↓

Daniels21

Higher levels when bacteria in sputum

Dentener54

↓

Dev20

Higher levels in S. pneumoniae and M. catarrhalis

infection

Gompertz16

Purulent >mucoid sputum ↓

Hill55

↑ ↔: ECOPD with and without α1-antitrypsindeficiency ↓

Hurst56

↑

Hurst12

↑

Kherad33

↔:with or without proven viral infection

Koutsokera6 ↓

Krommidas57

↓

Lazar58

ECOPD>controls

Perera44

↑

Phua14

Pneumonia>ECOPD

Quint32

↑

Sala9 ECOPD>stable COPD, ECOPD>controls ↓

Sethi26

↑ ↓

Spruit59

ECOPD>stable COPD, ECOPD>controls ↓

Stockley17

Purulent>mucoid sputum

Stolz36

Higher levels in type I ECOPD

Higher levels in mild to moderate COPD

↓

Tkacova11

ECOPD patients GOLD II<III<IV

Weis18

↔: ECOPD with increased sputum purulence,

pneumonia

Symbols: ↔: no difference, ↑: increase, ↓: decrease

Page 28 of 58


29

Tab

le 2

Ass

essm

ent

of

Pro

calc

itonin

at

EC

OP

D o

nse

t (c

ross

-sect

ional

des

ign)

and d

uri

ng t

he

cours

e of

EC

OP

D (

longit

udin

al d

esi

gn).

An e

xte

nded

ver

sion o

f th

is T

able

is

incl

uded

in t

he

Onli

ne

Supple

ment

of

this

pap

er.

Refe

ren

ce

Cou

rse

: fr

om

base

lin

e to

EC

OP

D o

nse

t

Co

mp

aris

on

s at

EC

OP

D o

nse

t C

ou

rse

: d

urin

g

EC

OP

D

Bozi

novsk

i22

↔

Chri

st-

Cra

in39

44.8

% h

ad>

0.1

µg/L

, 17.2

% h

ad >

0.2

5 µ

g/L

Dan

iels

21

↔

: P

rese

nce

or

abse

nce

of

sputu

m b

acte

ria

Dau

bin

28

↔

: E

CO

PD

bac

teri

olo

gic

ally

confi

rmed

or

not

Kher

ad3

3

↔

: E

CO

PD

ass

oci

ate

d o

r not

wit

h a

vir

us

Phua1

4

E

CO

PD

<pneum

onia

Sto

lz3

8

51%

had

<0.1

µg/L

, 29%

had

0.1

-0.2

5,

20%

had >

0.2

5

Sto

lz3

6

↔

: G

OL

D s

tages

↓

Sy

mb

ols

: ↔

: no d

iffe

rence

, ↓:

dec

reas

e

Pag

e 29

of

58


30

Tab

le 3

Stu

die

s in

vest

igat

ing t

he

pro

gnost

ic v

alue

of

syst

emic

bio

mar

ker

s fo

r cli

nic

al o

utc

om

es

Param

ete

r

Stu

die

d B

iom

ark

ers

Dia

gnosi

s C

RP

12,2

4,

IL-6

12,

MP

IF1

2,

SP

-D6

0 (

36 b

iom

arker

s as

sess

ed b

y H

urs

t et

al.

12*)

Eti

olo

gy

BN

P2

7,

CR

P16

-20,2

2-2

6,3

2,3

3,6

1,

EC

P3

0,

Fib

rinogen

31

,62,

Glu

cose

23,

IL-6

25

,31

,32

,34,

Insu

lin

23,

IP-1

03

2,

Lep

tin

23,

Pro

AD

M2

9,

Pro

ET

-12

9,

Pro

cal

cit

onin

21

,28

,29,

SA

A22,

s IL

5R

α3

0, sT

NF

-R55

23, sT

NF

-R75

23

Sev

erit

y

BN

P2

7,

Copep

tin

7,3

6, C

RP

22

,26,3

6,

Pro

AD

M2

9,

Pro

ET

-12

9,

PC

T 2

2,2

8,3

6,

SA

A2

2,

s T

RE

M-1

14 (

36

bio

mar

kers

ass

esse

d b

y H

urs

t et

al.

12*)

Guid

ance

of

anti

bio

tic

use

C

RP

21,

PC

T2

1,3

8-4

0,

s T

RE

M-1

14

Dura

tion o

f hosp

ital

izati

on

Alb

um

in41,

BN

P27,

Copep

tin

36,

CR

P36,

PC

T28

,36,

Pro

AD

M2

9,

Pro

ET

-12

9,

s T

RE

M-1

14, T

roponin

37,4

2

Dura

tion o

f re

covery

/Com

pli

cati

ons

Copepti

n36,

CR

P6,3

6,3

7,4

4, F

ibri

no

gen

6,

Glu

cose

63,

IL-6

6,4

4,

PC

T28

,36,

SA

A6,

s T

RE

M-1

14,

TN

Fα

6

EC

OP

D f

requen

cy/r

ecurr

ence

A

lbum

in41,

CR

P4

4,

IL-6

44,

PC

T28

Mort

alit

y/S

urv

ival

B

NP

27,

CR

P7,2

9,3

6,4

5,

PC

T2

8,2

9,

Pro

AD

M2

9,

Pro

ET

-12

9,

s T

RE

M-1

14,

Tro

ponin

37

,42,4

5,4

6

*N

ote

: th

e st

udy o

f H

urs

t et

al.

12 i

nves

tigat

ed t

he

role

of

36

pla

sma

bio

mar

ker

s (C

RP

, IL

6,

MP

IF-1

, P

AR

C, ad

iponec

tin

, sI

CA

M-1

, β

DN

F,

EN

A-7

8, E

ota

xin

-

2,

Erb

-B2,

fibro

nec

tin,

IFN

-γ, IL

-1β

, IL

-1R

a, I

L-8

, IL

-12p40,

IL-1

5,

IP-1

0,

ITA

C,

MC

P-1

, M

IP-1

β, M

MP

-9,

MP

O, P

rola

ctin

, R

AN

TE

S,

L-s

elec

tin,

TG

F-α

,

TIM

P-1

, T

NF

-α, T

NF

R1, T

NF

R2,

VE

GF

) in

the

confi

rmat

ion o

f E

CO

PD

dia

gnosi

s an

d i

n t

he

det

erm

inat

ion o

f it

s se

ver

ity. In

the

pre

sent

table

th

e bes

t per

form

ing m

ark

ers

of

this

stu

dy w

ere

incl

uded

.

Ab

bre

via

tion

s: B

NP

: bra

in n

atri

ure

tic

pep

tide,

βD

NF

: bra

in-d

eriv

ed n

euro

trophic

fac

tor,

CR

P:

C-r

eact

ive

pro

tein

, E

CP

: eo

sinop

hil

cat

ionic

pro

tein

, E

rb-B

2;

eryth

robla

stic

leu

kem

ia v

iral

onco

gen

e ho

molo

g 2

, IL

: in

terl

eukin

, IP

-10

: IF

N-γ

induce

d p

rote

in 1

0, IT

AC

: IF

N γ

indu

cible

T c

ell

α c

hem

oat

trac

tant,

MP

IF-1

:

Myel

oid

pro

gen

itor

inhib

ito

ry f

acto

r-1,

PA

RC

: pulm

onar

y a

nd a

ctiv

atio

n-r

egula

ted c

hem

ok

ine,

Pro

AD

M: p

ro-a

dre

nom

edull

in, P

roE

T1:

pro

endoth

elin

1,

PC

T:

pro

calc

itonin

, S

AA

: se

rum

am

ylo

id A

, sI

L-5

Rα

: so

luble

inte

rleu

kin

5 r

ecep

tor

α, sT

RE

M-1

: S

olu

ble

form

of

the

trig

ger

ing r

ecep

tor

expre

ssed

on

myel

oid

cel

ls, T

NF

α:

tum

or

nec

rosi

s fa

cto

r a,

TN

T:

tro

ponin

, V

EG

F:

vas

cula

r en

do

thel

ial

gro

wth

fac

tor

Pag

e 30

of

58


31

Tab

le 4

Syst

emic

bio

mar

ker

s m

easu

red d

uri

ng c

linic

ally

sta

ble

CO

PD

as

pre

dic

tors

of

EC

OP

D-r

ela

ted o

utc

om

es

Bio

mark

er

Ref

. E

nd

poin

t C

om

men

t

α1-a

nti

tryp

sin

P

64

CO

PD

hosp

ital

izat

ions

In

crea

sed l

evel

s w

ere

asso

ciat

ed w

ith

the

inci

den

ce o

f C

OP

D h

osp

ital

izat

ion

Ceru

lop

lasm

inP

64

CO

PD

hosp

ital

izat

ions

Incr

ease

d l

evel

s w

ere

asso

ciat

ed w

ith

the

inci

den

ce o

f C

OP

D h

osp

ital

izat

ion

CR

PS

65

CO

PD

hosp

ital

izat

ion, d

eath

In

crea

sed l

evel

s is

a s

tron

g l

ong-t

erm

pre

dic

tor

of

CO

PD

ho

spit

aliz

atio

n a

nd d

eath

6

6

EC

OP

D f

requ

ency

N

o d

iffe

ren

ce b

etw

een f

requen

t (≥

3/y

ear)

or

infr

equen

t (≤

2/y

ear)

exac

erbat

ors

CR

PP

67

EC

OP

D f

requ

ency

E

levat

ed i

n f

requen

t ex

acer

bat

ors

C

XC

L-1

6P

67

EC

OP

D f

requ

ency

N

o a

sso

ciat

ion

rep

ort

ed

ET

-1P

68

EC

OP

D f

requ

ency

N

o a

sso

ciat

ion

rep

ort

ed

Fib

rin

og

enP

69

EC

OP

D f

requ

ency

F

requ

ent

exac

erbat

ors

(≥

2.5

2/y

) had

a f

aste

r ri

se o

ver

tim

e in

pla

sma

fibri

nogen

6

4

CO

PD

hosp

ital

izat

ions

Incr

ease

d l

evel

s w

ere

asso

ciat

ed w

ith

the

inci

den

ce o

f C

OP

D h

osp

ital

izat

ion

7

0

EC

OP

D f

requ

ency

, se

ver

ity

Incr

ease

d l

evel

s w

ere

asso

ciat

ed w

ith

EC

OP

D f

requen

cy a

nd

the

dev

elo

pm

ent

of

sever

e E

CO

PD

Hap

tog

lob

inP

64

CO

PD

hosp

ital

izat

ions

Incr

ease

d l

evel

s as

soci

ated

wit

h i

nci

den

ce o

f C

OP

D h

osp

ital

izat

ion

IL

-6S

44

EC

OP

D r

ecu

rren

ce

No a

sso

ciat

ion

rep

ort

ed

LB

PP

70

EC

OP

D f

requ

ency

N

o r

elat

ion w

ith t

he

occ

urr

ence

of

sever

e or

moder

ate

EC

OP

D. N

o a

sso

ciat

ion

wit

h t

ime

to f

irst

EC

OP

D.

MB

LP

71

EC

OP

D f

requ

ency

N

o a

sso

ciat

ion

rep

ort

ed

MC

P 4

P

67

EC

OP

D f

requ

ency

N

o a

sso

ciat

ion

rep

ort

ed

NA

P 2

P

67

EC

OP

D f

requ

ency

N

o a

sso

ciat

ion

rep

ort

ed

NG

AL

P

72

EC

OP

D f

requ

ency

H

igher

lev

els

wer

e as

soci

ated

wit

h f

requ

ent

exac

erbat

ions

O

roso

mu

coid

P

64

CO

PD

hosp

ital

izat

ions

Incr

ease

d l

evel

s w

ere

asso

ciat

ed w

ith

the

inci

den

ce o

f C

OP

D h

osp

ital

izat

ion

Ost

eop

rote

gri

nP

67

EC

OP

D f

requ

ency

In

crea

sed l

evel

s w

ere

asso

ciat

ed w

ith

fre

qu

ent

EC

OP

D

SP

-DS

73

EC

OP

D f

requ

ency

In

crea

sed r

isk o

f E

CO

PD

wit

h v

alues

> 9

5th p

erce

nti

le (

for

non-s

moker

s)

sTN

F-R

1P

67

EC

OP

D f

requ

ency

In

crea

sed l

evel

s w

ere

asso

ciat

ed w

ith

fre

qu

ent

EC

OP

D

sTN

F-R

55

P

70

EC

OP

D f

requ

ency

N

o r

elat

ion w

ith t

he

occ

urr

ence

of

sever

e or

moder

ate

EC

OP

D. N

o a

sso

ciat

ion

wit

h t

ime

to f

irst

EC

OP

D.

sTN

F-R

75

P

70

EC

OP

D f

requ

ency

N

o r

elat

ion w

ith t

he

occ

urr

ence

of

sever

e or

moder

ate

EC

OP

D. N

o a

sso

ciat

ion

wit

h t

ime

to f

irst

EC

OP

D.

Ab

bre

via

tion

s: C

RP

: C

rea

ctiv

e p

rote

in, E

T-1

: E

ndoth

elin

-1,

LB

P:

lipopoly

sacc

har

ide

bin

din

g p

rote

in, M

BL

: m

anno

se b

indin

g l

ecti

n, M

CP

: M

onocy

te

chem

oat

trac

tant

pro

tein

, N

AP

: N

eutr

ophil

act

ivat

ing p

epti

de

NA

P,

NG

AL

: N

eutr

oph

il g

elat

inas

e as

soci

ated

lip

oca

lin

, S

P-D

: su

rfac

tant

pro

tein

D, s-

TN

F-R

:

solu

ble

rec

epto

r o

f tu

mor

nec

rosi

s fa

cto

r S

ym

bols

: S

: se

rum

, P

: pla

sma

Pag

e 31

of

58


254x190mm (96 x 96 DPI)

Page 32 of 58


ONLINE SUPPLEMENT

SYSTEMIC BIOMARKERS IN EXACERBATIONS OF COPD: THE

EVOLVING CLINICAL CHALLENGE

Angela Koutsokera, MD1, [email protected]

Daiana Stolz, MD, FCCP2, [email protected]

Stelios Loukides, MD, FCCP3, [email protected]

Konstantinos Kostikas, MD, FCCP3, [email protected]

From the 1Service de Pneumologie et Rehabilitation Respiratoire, Hôpital de Rolle,

Switzerland; 2Clinic for Pulmonary Medicine and Respiratory Cell Research,

University Hospital Basel, Switzerland; 32

nd Respiratory Medicine Department,

University of Athens Medical School, Athens, Greece

Correspondence to:

Dr. Konstantinos Kostikas

Stamouli 3, Karditsa 43100, Greece

Tel + 30-6944780616, Fax +30-2441022370, e-mail [email protected]

Short Title: Systemic Biomarkers in COPD Exacerbations

Conflict of Interest: Dr. Stolz has received speakers’ honoraria from BRAHMS AG

(the manufacturer of pro-adrenomedullin, copeptin, pro-endothelin, and procalcitonin

assays) and was sponsored by BRAHMS AG for speaking engagements and research

(unrestricted grant). None of the other authors has any conflict of interest related to

the present manuscript.

Page 33 of 58


Ta

ble

A

Ass

essm

ent

of

CR

P a

t E

CO

PD

on

set

(cro

ss-s

ecti

on

al d

esig

n)

and

du

rin

g t

he

cou

rse

of

EC

OP

D (

longit

ud

inal

des

ign)

Stu

dy

S

am

ple

C

ou

rse:

fro

m

ba

seli

ne

to

EC

OP

D o

nse

t

EC

OP

D o

nse

t

Lev

els

(mg

/L)

Co

mp

ari

son

s (c

ross

-sec

tio

na

l)

Co

urs

e:

du

rin

g E

CO

PD

Co

mm

ent

Bat

ho

orn

1

S

↔

#3

.6 (

1.5

–1

7.1

)

Bir

can

2

S

‡

36

.8(4

3.9

) E

CO

PD

>co

ntr

ols

, E

CO

PD

>st

able

CO

PD

EC

OP

D<

pneu

mo

nia

R

etro

spec

tive

stud

y

Bo

zino

vsk

i3

S

↑

†1

2.5

E

CO

PD

>st

able

CO

PD

↓

GC

S:

Yes

↔:

level

I,

level

II/I

II E

CO

PD

bac

teri

al>

no

n-b

acte

rial

EC

OP

D

Bre

kke4

S

59

% a

nd

53

% h

ad ≥

50

mg/l

Chri

st-C

rain

5

P

‡

97

.8 (

10

6.1

), 8

2.8

(9

3.9

)

Cre

utz

ber

g6

P

‡

33

.3 (

25

.9)

EC

OP

D>

contr

ols

↓

Fel

l b

y D

3.

GC

S:

Yes

↔:W

ith o

r w

itho

ut

bac

teri

al i

nfe

cti

on

Cro

oks7

S

€1

35±

36

.2

↓

Fel

l b

y D

7.

GC

S:

N/R

Dan

iels

8_ENRE

F_32

S

1

7%

≤5

, 4

6%

6-5

0, 3

7%

>5

0 m

g/l

H

igher

lev

els

when b

acte

ria

in s

putu

m

Den

tener

9

P

N

/R

↓

Fel

l b

y D

3.

GC

S:

Yes

Dev

10

S

R

20

-38

8 (

infe

ctio

n)

<1

0-3

24

(no

pro

ven

in

fect

ion)

Hig

her

lev

els

in S

.pneu

mo

nia

e an

d

M.c

atar

rhal

is i

nfe

cti

on

Go

mp

ertz

11

S

#

16

.7 (

6.2

– 4

0.3

) P

uru

lent,

4.6

(1.0

– 9

.1)

Muco

id

Puru

lent

>m

uco

id s

putu

m

↓

Fel

l b

y D

56

. G

CS

: N

/R

Hil

l12

S

↑

§3

4.0

(18.5

) A

AT

def

42

.9(1

9.3

) no

AA

Td

ef

↔:

EC

OP

D w

ith a

nd

wit

ho

ut

AA

T

def

icie

ncy

↓

Fel

l af

ter

trea

tmen

t, b

y D

14

fo

r th

e

AA

T d

ef.

gro

up

. G

CS

: N

o

Hurs

t13

S

↑

‡4

8.5

(36

.1)

Hurs

t14

P

↑

#1

5.6

(4

.5–

74

.0)

Kher

ad1

5

S

£3

5(1

-31

3)

↔:w

ith o

r w

itho

ut

pro

ven v

iral

infe

ctio

n

Ko

uts

oker

a16

S

€

5.4

(1.2

)

↓

Fel

l b

y D

3.

GC

S:

Yes

Kro

mm

idas1

7

S

#

2.0

9 (

0.7

8-6

.90

)

↓

GC

S:

Yes

Laz

ar1

8

N/R

‡2

4.5

(23.6

)

EC

OP

D>

contr

ols

Per

era1

9

S

↑

# 6

.5 (

3.8

-11

.8)

67

% r

ecei

ved

GC

S

Phua2

0

S

£1

.9(0

–12

.9)

Pneu

mo

nia

>E

CO

PD

Quin

t21

S

↑

7.0

0 m

g/l

(2

.5 –

14

.0)

Sal

a22

P

EC

OP

D>

stab

le C

OP

D E

CO

PD

>co

ntr

ols

↓

GC

S Y

es

Pag

e 35

of

58


Set

hi2

3

S

↑

¥2

.12 (

1.7

–2.6

5)

↓

GC

S N

/R

Sp

ruit

24

S

#

28

(1

1–

86

) E

CO

PD

>st

able

CO

PD

EC

OP

D>

contr

ols

↓

Fel

l b

y D

3.

GC

S Y

es

Sto

ckle

y2

5

S

#

4.9

(1.0

-10

.2)

muco

id

14

.5(6

.2-3

5.8

) p

uru

lent

Puru

lent>

mu

coid

sp

utu

m

Sto

lz2

6

N/R

#1

6 (

5–

53

), 2

2(7

–62

)

Sto

lz2

7

N/R

#1

7.1

(5

.2–

55

.9)

Sto

lz2

8

P

#

26

.5 (

7.4

-60

.1)

Hig

her

lev

els

in t

yp

e I

EC

OP

D

Hig

her

lev

els

in m

ild

to

mo

dera

te C

OP

D

↓

Fel

l b

y D

14

. G

CS

Yes

Tkac

ova2

9

S

£1

7.9

(0.1

-28

2.8

) E

CO

PD

pat

ients

GO

LD

II<

III<

IV

Wei

s30

S

4

6%

had

0-1

0m

g/L

↔

: E

CO

PD

wit

h i

ncr

ease

d s

putu

m

puru

lence

, p

neu

mo

nia

Ab

bre

via

tio

ns:

AA

T d

ef.:

A1

anti

tryp

sin d

efi

ciency,

GC

S:

syst

em

ic g

luco

cort

ico

ster

oid

s, P

: p

lasm

a, S

: se

rum

, N

/R:

no

t re

po

rted

Sy

mb

ols

:↔:

no

dif

fere

nce

, ↑:

incr

ease

, ↓:

dec

reas

e, #

Med

ian (

inte

rquar

tile

ran

ge)

, †

med

ian,

‡m

ean (

SD

), €

mea

n±

SE

M,

§ a

ver

age(

SE

), ¥

geo

metr

ic m

ean (

95

% C

I),

£

med

ian (

ran

ge)

Pag

e 36

of

58


Ta

ble

B

Ass

essm

ent

of

Pro

calc

ito

nin

at

EC

OP

D o

nse

t (c

ross

-sec

tio

nal

des

ign

) an

d d

uri

ng t

he

cou

rse

of

EC

OP

D (

longit

udin

al d

esig

n)

Stu

dy

Sa

mp

le

Co

urs

e: f

rom

ba

seli

ne

to

EC

OP

D o

nse

t

EC

OP

D o

nse

t

Lev

els

(µg/L

) C

om

pa

riso

ns

(cro

ss-s

ecti

on

al)

C

ou

rse:

du

rin

g

EC

OP

D

Co

mm

ent

Bo

zin

ovsk

i3

S

↔

N/R

Ch

rist

-Cra

in5

S

‡

1.6

(4.2

), 1

.6(7

.7)

4

4.8

% h

ad>

0.1µ

g/L

1

7.2

% h

ad >

0.2

5

Dan

iels

8

S

€

0.1

6(0

.42

), 0

.10

(0.1

9)

↔:

Pre

sen

ce o

r ab

sence

of

spu

tum

bac

teri

a

Lev

els

of

the

do

xycy

clin

e an

d

pla

ceb

o g

rou

ps

resp

ecti

vel

y

Dau

bin

31

S

#

0.0

96

(0.0

65

-0.1

78

) ↔

: E

CO

PD

bac

teri

olo

gic

ally

con

firm

ed o

r n

ot

7

7%

use

d G

CS

Kh

erad

15

S

£

0.0

8(0

.01

-17

.0)

↔:

EC

OP

D a

sso

ciat

ed o

r no

t

wit

h a

vir

us

Ph

ua2

0

S

£

0.2

5(0

–0

.78)

EC

OP

D<

pn

eum

on

ia

9

3%

use

d G

CS

Sto

lz26

S

#

0.0

96

(0.0

70

-0.2

00

)µg/L

5

1%

had

<0

.1 µ

g/L

, 2

9%

had

0

.1-0

.25

, 2

0%

had

>0

.25

Sto

lz27

N/R

#0

.09

6 (

0.0

70

–0

.20

0)

S

tolz

28

P

#

0.0

88

(0.0

53

-0.1

61

) ↔

: G

OL

D s

tages

↓

Fel

l b

y D

14

. 8

8%

use

d G

CS

Ab

bre

via

tio

ns:

GC

S:

syst

emic

glu

coco

rtic

ost

eroid

s,P

: p

lasm

a, S

: se

rum

, N

/R:

not

rep

ort

ed

Sy

mb

ols

: ↔

: n

o d

iffe

ren

ce, ↑

: in

crea

se, ↓:

dec

reas

e, #

Med

ian

(in

terq

uar

tile

ran

ge)

, †

med

ian

, ‡

mea

n (

SD

), €

mea

n±

SE

M,

§ a

ver

age

(SE

), ¥

geo

met

ric

mea

n

(95

% C

I),

£ m

edia

n (

ran

ge)

Pag

e 37

of

58


Table C

Assessment of systemic biomarkers* at ECOPD onset (cross-sectional design)

Biomarker Ref. Comparisons at ECOPD onset

A1 antitrypsinS

12 ECOPD without deficiency>ECOPD with deficiency

BNPP

27 ↔:ECOPD with and without cardiomyopathy

27

↔: ECOPD with steady state PAH, without PAH

27

↔: ECOPD with positive or negative bacterial sputum cultures

CopeptinS

32 ECOPD>controls

CopeptinP

28 ↔: COPD stages

ECPS

33,34

ECOPD>controls (Controls

33: patients with pulmonary oedema,

pulmonary embolism, interventricular communication)

34

↔:ECOPD, healthy smokers

34

Higher levels when respiratory viruses were detected

33

ECOPD>stable COPD

ErythropoietinP

22 ECOPD<stable COPD

22

ECOPD<never smokers

22

ECOPD<smokers

E-selectinS

35 ECOPD>controls

FibrinogenP

36 Higher levels: purulent sputum, increased cough and presence of

a cold

GlucoseP

6 ECOPD>controls

6 ↔: ECOPD with and without bacterial infection

GM-CSFS

37 ECOPD>stable COPD

IgES

33 ECOPD>controls (Controls: patients with pulmonary oedema,

pulmonary embolism, interventricular communication)

IGF-IS

24 ↔: ECOPD, controls

IGF-IP

38 ECOPD<controls

38

ECOPD emphysema<chronic bronchitis

IL-1βS

38 ECOPD>controls

39

↔:ECOPD, asthma exacerbations

IL-1RaS

39 ECOPD>asthma exacerbations

IL-4S

39 ECOPD>asthma exacerbations

IL-6S

38,40 ECOPD>controls

24

↔: ECOPD, controls

19,36,38

ECOPD>stable COPD

24

↔:ECOPD, stable COPD

29

↔: ECOPD GOLD stages (Not specified at which time point

lung functions used for GOLD characterization were done)

39


41

ECOPD with both rhinovirus and H. influenzae> ECOPD

without both pathogens

IL-8S

24,35,38 ECOPD>controls

24

ECOPD>stable COPD

39

ECOPD>asthma exacerbations

IL-10S

24 ↔: ECOPD, stable COPD

InsulinS

6 ECOPD>controls

6

↔: ECOPD with and without bacterial infection

LeptinS

38,42 ECOPD>controls

38,42

ECOPD>stable COPD

LeptinP

6 ECOPD>controls

6 ↔: ECOPD with and without bacterial infection

LFA-1∞ adhesion molecule, PMN

43

ECOPD<Stable COPD, ECOPD<controls

of 58


L-selectin∞ adhesion molecule, PMN

43

↔: ECOPD, stable COPD, controls

Mac-1∞ adhesion molecule, PMN

43

ECOPD<Stable COPD, ↔: ECOPD, controls

MPOS

33 ECOPD>controls (Controls: patients with pulmonary oedema,

embolism, interventricular communication)

33

ECOPD>stable COPD

33

↔: ECOPD smokers, ECOPD non smokers

Nitrite/nitrateS

40 ECOPD>controls

40

ECOPD>stable COPD

ProADMP

44 Elevated in 87.4% of ECOPD patients

44

No correlation with ECOPD stage

ProET-1P

44 Elevated in 87.4% of ECOPD patients

Protein thiolsP

45 ECOPD<controls

45

↔:ECOPD current<ex-smokers

SAA 3

ECOPD>stable COPD (Mean time from ECOPD onset to

obtaining serum 6.2 days)

3

ECOPD level II/III>level I

3

Bacteria-associated ECOPD>nonbacterial ECOPD

sICAMS

35 ECOPD>controls

sICAM-1P

43 ↔: ECOPD, stable COPD, ECOPD<controls

sIL-5RαS

34 ECOPD>controls

34

↔: ECOPD, healthy smokers

SP-DS

46 ECOPD> stable COPD> controls

sTNF R55P


47

ECOPD>controls

6 ↔: patients with and without bacterial infection

sTNF R75P


47

ECOPD>controls

6 ↔: patients with and without bacterial infection

TBA-MDA ad.P

45 ECOPD>controls

TEACP

45,48 ECOPD<controls

45

ECOPD smokers<ex-smokers

45

↔:ECOPD on or without GCS

TNFαS

38,40,42 ECOPD>controls

42

ECOPD>stable COPD

40

↔:ECOPD, stable COPD

24

Undetectable levels

39


TNFαP

47 ECOPD>controls (smokers, non smokers)

sTREM-1S

20 ECOPD>controls

20

ECOPD type I> type II/III

20

ECOPD type I>asthma exacerbations

20

↔: ECOPD type II+III, asthma exacerbations

20

ECOPD type II+III<pneumonia

20

↔: ECOPD type I, pneumonia

*CRP and PCT are discussed in Tables 1 and 2 respectively Abbreviations: BNP: B natriuretic peptide, ECP: Eosinophil cationic protein, GCS:

glucocorticosteroids, GSHPx: Glutathione peroxidase, GM-CSF: granulocyte macrophage

colony-stimulating factor, ICU: intensive care unit, IgE: immunoglobulin E, IGF-I: insulin-

like growth factor, IL: interleukin, IL-1Ra: interleukin 1 receptor antagonist, LFA-1:

lymphocyte function-associated antigen-1, Mac-1: MPO: myeloperoxidase, PAH: pulmonary

arterial hypertension, PMN: polymorphonuclear neutrophils, proADM: pro-adrenomedullin,

proET-1: proendothelin 1, Ref.: references, SAA: serum amyloid A, sICAM: soluble

intercellular adhesion molecule-, sIL-5Rα: soluble interleukin 5 receptor α, sTNF R: soluble

tumor necrosis factor receptor, TBA-MDA ad.: Thiobarbituric acid, malondialdehydeadducts,

of 58


TEAC: Trolox equivalent antioxidant capacity, TNFα: tumor necrosis factor α, SP-D:

surfactant protein D, sTREM-1: Soluble form of the triggering receptor expressed on myeloid

cells. Symbols: ↔: no difference, P: plasma, S: serum, ∞: biomarkers of circulating cells

of 58


Ta

ble

D

Ass

essm

ent

of

syst

emic

bio

mar

ker

s* f

rom

bas

elin

e to

war

ds

EC

OP

D o

nse

t an

d d

uri

ng E

CO

PD

(lo

ngit

udin

al d

esig

n)

Bio

mark

er

Ref

. C

ou

rse:

Ba

seli

ne-

On

set

Co

urs

e: d

uri

ng

EC

OP

D

Sy

stem

ic G

CS

du

rin

g E

CO

PD

Co

mm

ents

A1

-AC

PS

7

↓

N

/R

Fel

l b

y D

14

Ad

ipo

nec

tin

P

14

↑

17

↓

Y

es

Fel

l b

y t

reat

men

t co

mp

leti

on

an

d s

ym

pto

m r

eso

luti

on

A1

an

titr

yp

sin

S

12

P

eak:

D3

, fa

llin

g t

her

eaft

er

Yes

S

ubje

cts

wit

h A

1 a

nti

tryp

sin

def

icie

ncy

Am

ph

ireg

uli

nP

14

↔

A1

-PIS

7

↓

N

/R

Fel

l b

y D

14

BD

NF

P

14

↔

β-N

GF

P

14

↔

BN

PP

27

↓

N

/R

Fel

l b

y D

14

-18

Cat

alas

eP

49

↔

N

/R

Tim

e p

oin

ts:

D0

, per

iod

aft

er t

reat

men

t

Co

pep

tin

P

28

↓

8

8%

F

ell

by D

14

EC

PS

34

↔

U

sual

ly

Tim

e p

oin

ts:

D1

, ho

spit

al d

isch

arge

EN

A-7

8P

14

↔

Pag

e 41

of

58


Eo

taxin

-2P

14

↓

Ery

thro

poie

tin

P

22

Yes

C

han

ge

of

level

s b

y M

3 a

fter

dis

char

ge

Erb

-B2

P

14

↔

E s

elec

tin

S

35

↔

Y

es

Tim

e p

oin

ts:

D1

,3,7

ET

-1P

50

↑

Fib

rin

ogen

P

36,5

1

↑

16

↓

Y

es

Fel

l b

y D

40

Fib

ron

ecti

nP

14

↔

Glu

cose

P

6

↓

Y

es

Fel

l b

y D

7

GS

HP

xP

49

↓

N

/R

Fel

l af

ter

trea

tmen

t

GR

dP

49

↓

N

/R

Fel

l af

ter

trea

tmen

t

IFN

-γP

14

↔

IGF

-IS

24

↑

Y

es

Sig

nif

ican

t ↑

bet

wee

n D

8-D

90

, b

ut

12

of

34

pat

ien

ts d

rop

ped

out

IGF

-IP

38

↓

Y

es

Fel

l b

y D

15

IL-1β

S

38

↓

Y

es

Fel

l b

y D

15

IL-1β

P

14

↔

Pag

e 42

of

58


IL-1

RaP

14

↑

IL-2

RγP

14

↔

IL-6

S

1,3

,13,1

9,2

1

↑

41

↔

19

N

o c

om

par

iso

n w

ith D

0

67

%

D7

<b

asel

ine

(bef

ore

EC

OP

D),

D1

4=

Bas

elin

e, D

35=

Bas

elin

e

16,1

7,3

8,5

1

↓

Y

es16,1

7,3

8,Y

som

e51

16:

fell

by D

3

24,4

0

↔

Y

es

Tim

e p

oin

ts:2

4:

D3

,8,9

0,

40:

D0

,D1

4,W

6

IL-6

P

14

↑

52

↓

Y

es

Fel

l b

y D

2

IL-8

S

24

↔

Y

es

Tim

e p

oin

ts:

D3

,8,9

0 (

12

of

34

pat

ien

ts d

rop

ped

ou

t)

35,3

8

↓

Y

es

35:

fell

by D

7

IL-8

P

14

↔

52

↓

Y

es

Fel

l b

y D

2

IL-1

0S

24

↔

Y

es

Tim

e p

oin

ts:

D3

,8,9

0

IL-1

2p

40

P

14

↔

IL-1

5P

14

↔

Pag

e 43

of

58


IL-1

7P

14

↔

Insu

lin

S

6

↔

Y

es

Gra

du

al d

rop

by D

7,

bu

t n

o s

tati

stic

ally

sig

nif

ican

t

IP-1

0S

21

↑

IP-1

0P

14

↑

ITA

CP

14

↔

LB

PP

9

↓

Y

es

Fel

l b

y D

7

Lep

tin

S

38

↓

Y

es

Fel

l b

y D

15

Lep

tin

P

6

↓

Y

es

Dec

reas

ed g

radu

ally

th

rou

gh

ou

t E

CO

PD

17

↓

Y

es

Fel

l b

y t

reat

men

t co

mp

leti

on

an

d s

ym

pto

m r

eso

luti

on

L-s

elec

tin

P

14

↔

LT

B4

P

52

↓

Y

es

Rem

ain

ed s

tab

le u

nti

l D

2 a

nd

fel

l b

y 8

W

MC

P-1

P

14

↔

MD

AP

49

↑

N

/R

Incr

ease

d a

fter

tre

atm

ent

Mel

ato

nin

S

49

↑

N

/R

Incr

ease

d a

fter

tre

atm

ent

(wit

hin

10

day

s)

MIP

-1β

P

14

↔

MM

P-9

P

14

↔

Pag

e 44

of

58


MP

IF-1

P

14

↑

MP

OP

14

↔

Nit

rite

/nit

rate

S

40

↔

Y

es

Tim

e p

oin

ts:

D0

, D

14

, W

6

Ox

idat

ive

stre

ssS

16

↔

Y

es

Tim

e p

oin

ts:

D0

,3,1

0,4

0

PA

RC

P

14

↑

Pro

ET

1P

44

↓

Y

es s

om

e F

ell

by D

14

-18

Pro

lact

inP

14

↔

Pro

AD

MP

44

↓

Y

es s

om

e F

ell

by D

14

-18

RA

NT

ES

P

14

↔

SA

AS

3

↑

Mea

n t

ime

fro

m E

CO

PD

on

set

to s

eru

m s

amp

lin

g:

6.2

day

s

3,1

6

↓

Y

es

16F

ell

by D

10

sIC

AM

S

1

↔

35

↓

Y

es

Fel

l b

y D

7.

On

ad

mis

sio

n 6

pat

ients

wer

e al

read

y o

n o

ral

GC

S

sIC

AM

-1P

14

↑

sIL

1 R

IIP

9

↑

Y

es

Incr

ease

d b

y D

5 a

nd

rem

ain

ed s

table

bet

wee

n D

5-7

sIL

5 Rα

S

34

↓

Y

es u

sual

ly

Fel

l b

y h

osp

ital

dis

char

ge

Pag

e 45

of

58


SL

PIP

52

↔

Y

es

Tim

e p

oin

ts:

D0

, D

2, 8

W a

fter

dis

char

ge

SO

DP

49

↓

N

/R

Dec

reas

ed a

fter

tre

atm

ent

TB

A-M

DA

ad.P

45

↓

6

of

13

F

ell

wit

hin

12

h,

no

ch

ange

bet

wee

n 1

2h

an

d 4

8h

sTN

F R

55

P

6,9

in

itia

l↑, ↓

Y

es

Ris

e bet

wee

n D

1-3

, d

ecre

ase

ther

eaft

er b

ut

D1=

D7

47

↔

A

vo

ided

T

ime

po

ints

: ad

mis

sio

n, p

ost

tre

atm

ent

sTN

F R

75

P

47

↔

Y

es

Tim

e p

oin

ts:

6 :

D1

,3,5

,7,

47:a

dm

issi

on

, p

ost

tre

atm

ent

6

in

itia

l↑, ↓

Y

es

Sta

tist

ical

sig

nif

ican

ce n

ot

rep

ort

ed

9

in

itia

l↑, ↓

Y

es

Ris

e bet

wee

n D

1-3

, d

ecre

ase

ther

eaft

er b

ut

D1=

D7

TE

AC

P

45

↑

6

of

13

N

o c

han

ge

un

til

D2

, in

crea

sed

D5

-10

lat

er

TIM

P-1

P

14

↔

TG

F-α

P

14

↔

TN

Fα

S

1

↔

16

In

itia

l ↓

, tr

end

of ↑

ther

eaft

er

Yes

R

edu

ced

by D

3 a

nd

10

, n

o d

iffe

ren

ce b

etw

een

D0

an

d D

40

17,3

8

↓

Y

es

38R

edu

ced

by D

15

40

↔

Y

es

Tim

e p

oin

ts:

D0

,D1

4,W

6

Pag

e 46

of

58


TN

F-α

P

14

↔

52

↔

Y

es

Tim

e p

oin

ts:

D0

, D

2, 8

W a

fter

dis

char

ge

47

↓

A

vo

ided

F

ell

afte

r tr

eatm

ent

TN

FR

1P

14

↑

TN

FR

2P

14

↔

VE

GF

P

14

↔

*C

RP

an

d P

CT

are

dis

cuss

ed i

n T

ab

les

1 a

nd

2 r

esp

ecti

vel

y

Ab

bre

via

tio

ns:

A1

-AC

P:

A1

an

tich

ym

otr

yp

sin

, A

1-P

I: A

1 p

rote

ase

inh

ibit

or,

BD

NF

: B

rain

-der

ived

neu

rotr

op

hic

fac

tor,

β-N

GF

: N

erv

e gro

wth

fac

tor β

,

BN

P:

B n

atri

ure

tic

pep

tide,

D:

day

aft

er E

CO

PD

onse

t, E

CP

: E

osi

no

phil

cat

ionic

pro

tein

, E

NA

-78

: E

pit

hel

ial-

der

ived

neu

tro

phil

act

ivat

ing p

rote

in-7

8,

ET

-1:

end

oth

elin

1,

GC

S:

glu

coco

rtic

ost

ero

ids,

GS

HP

x:

Glu

tath

ion

e per

ox

idas

e, G

Rd:

Glu

tath

ion

e re

du

ctas

e, I

FN

- γ:

inte

rfer

on

γ,

IGF

-I:

Insu

lin

-lik

e gro

wth

fac

tor,

IL:

inte

rleu

kin

, IL

-2Rγ:

in

terl

eukin

2 r

ecep

tor γ,

IP

-10

: IF

Nγ

ind

uce

d p

rote

in 1

0,

ITA

C :

IF

Nγ

ind

uci

ble

T c

ell α

ch

emo

attr

acte

inas

e, L

BP

: li

po

poly

sacc

har

ide

bin

din

g p

rote

in,

LT

B4:

leuco

trie

ne

B4

, M

CP

-1 :

Mo

no

cyte

ch

emo

attr

acta

nt

pro

tein

1, M

DA

: m

alo

nd

iald

ehyd

e, M

IP-1β

: m

acro

ph

age

infl

amm

ato

ry p

rote

in-

1,

MM

P-9

: m

atri

x m

etal

lop

rote

inas

e 9

, M

PIF

-1 :

Myel

oid

pro

gen

itor

inh

ibit

ory

fac

tor-

1,

MP

O:

myel

op

erox

idas

e, ,

N/R

: no

t re

port

ed,

PA

RC

: P

ulm

on

ary a

nd

acti

vat

ion

-reg

ula

ted

ch

emo

kin

e, P

roA

DM

: p

road

ren

om

edu

lin

, R

AN

TE

S:

Reg

ula

ted

on

act

ivat

ion

norm

al T

-cel

l ex

pre

ssed

an

d s

ecre

ted

, R

ef.:

refe

ren

ces,

SA

A:

seru

m a

mylo

id A

, sI

CA

M:

solu

ble

inte

rcel

lula

r ad

hes

ion

mo

lecu

le-1

, S

LP

I: s

ecre

tory

leu

ko

cyte

pro

teas

e in

hib

ito

r, S

OD

: su

per

oxid

e

dis

mu

tase

, T

BA

-MD

A a

d.:

Thio

bar

bit

uri

c ac

id,

mal

ond

iald

ehyd

e ad

du

cts,

sT

NF

R:

solu

ble

tu

mo

r n

ecro

sis

fact

or

rece

pto

r, T

EA

C:

Tro

lox

eq

uiv

alen

t

anti

ox

idan

t ca

pac

ity,

TIM

P-1

: T

issu

e in

hib

ito

r of

met

allo

pro

tein

ase,

TG

F α

: tr

ansf

orm

ing g

row

th f

acto

r α

, T

NFα

: tu

mo

r n

ecro

sis

fact

or α

, V

EG

F:

vas

cula

r

end

oth

elia

l gro

wth

fac

tor,

W:

wee

ks

afte

r E

CO

PD

onse

t

Sy

mb

ols

: ↔

: n

o d

iffe

ren

ce, ↑

: in

crea

se, ↓:

dec

reas

e, S

: se

rum

, P

: pla

sma

Pag

e 47

of

58


Ta

ble

E

Co

rrel

atio

ns

of

syst

emic

bio

mar

ker

s at

EC

OP

D o

nse

t an

d d

uri

ng t

hei

r co

urs

e

Bio

mark

er

Sa

mp

le

Co

r.

Wit

h o

ther

bio

mark

ers

Wit

h c

lin

ica

l v

ari

ab

les

log

adip

onec

tin

P

-

CR

PS

17,

IL-6

S1

7,

TN

Fα

S17

BN

P

P

+

CR

PN

/R27,

PC

TN

/R27

Age2

7

Co

pep

tin

P

+

L

euco

cyte

co

unts

(w

eak c

orr

elat

ion)2

8

S

+

leu

cocy

te c

ou

nt2

,10, lo

g n

eutr

op

hil

co

unt2

9,

log l

epti

n P

17,

IL-

6S

13,

IL-8

SP

13,

PC

TS

8_ENREF_32

Cli

nic

al s

core

23

P

+

BN

P27,

EP

OP

22,

IL-6

P14,

PC

TN

/R26,

pro

AD

MP

44,

pro

ET

1P

44,

leu

cocy

te c

ou

nt

(wea

k c

orr

elat

ion

)28

N/R

+

B

NP

P27,

PC

TN

/R26

Un

ivar

iate

ass

oci

atio

n w

ith s

pu

tum

co

lou

r53

CR

P

S

- lo

g a

dip

onec

tin

P17

log

CR

P

S

- lo

g E

ryth

rocy

ticG

SH

Px

act

ivit

y29

∆ (

b-D

0)

CR

P

P

+

∆(b

-D0

) IL

-6P

14

EC

P

S

+

MP

OS

33

∆ (

b-D

0)E

T-1

P

-

∆ΕΤ

1S

P50

∆S

atO

250

EP

O

P

+

CR

PP

22,

circ

ula

tin

g n

eutr

oph

ils2

2

Pag

e 48

of

58


∆(b

-D0

)fib

rino

gen

P

+

∆

(b-D

0)

IL-6

P36

Glu

cose

P

+

s

TN

F R

55 (

on

Day

7 )

6

%F

M (

on

Day

7 )

6

Lep

tin

S

+

T

NFα

S38,4

2

∆le

pti

n

S

+

∆T

NFα

S38

P

+

CR

PS

17,

IL-6

S1

7,

TN

Fα

S17

lo

gle

pti

n

P

-

Die

tary

in

take/

RE

E r

atio

(on

Day

7)6

IgE

S

+

M

PO

S33

IGF

-I

S

+

Q

uad

rice

ps

pea

k t

orq

ue2

4

∆(b

-D0

)IL

-1R

a P

+

∆

(b-D

0)

IL-6

P14

S

+

CR

PS

13,

IL8

SP

13,

logle

pti

nP

17

P

+

CR

PP

14,

MP

IF-1

P14,

a n

etw

ork

of

seven

in

terr

elat

ed p

rote

ins

(co

mp

risi

ng I

L-1

Ra,

IL

-8,

IL-1

2,

IL-1

5,

IL-2

R,

NG

F,

and

amp

hir

egu

lin)P

14

IL-6

S

- L

og a

dip

on

ecti

n P

17

log

IL

-6

S

-

Qu

adri

ceps

pea

k t

orq

ue2

4

P

+

∆

Dysp

nea

52

∆IL

-6

P

-

∆

FE

V1

52

Pag

e 49

of

58


S

+

∆ (

b-D

0)

fib

rin

ogen

P36, ∆

(b

-D0

) IL

6S

P41

∆ i

n b

acte

rial

lo

ad21

P

+

∆ (

b-D

0)

CR

PP

14, ∆

(b-D

0)

fibri

no

gen

P36,∆

(b-D

0)

IL-1

RaP

14,

∆(b

-D0

) M

PIF

-1P

14

∆(b

-D0

)IL

-6

S

-

Bas

elin

e F

EV

141

log

IL

-8

S

-

Qu

adri

ceps

pea

k t

orq

ue2

4

∆ I

L-8

P

+

∆ D

ysp

nea

52

IP-1

0

S

+

V

iral

load

21

MP

IF-1

P

+

IL

-6P

14

∆(b

-D0

)MP

IF-1

P

+

∆

(b-D

0)

IL-6

P14

MP

O

S

+

EC

PS

S

+

BN

P27,

CR

PS

8,2

6_ENREF_51

, le

uco

cyte

co

un

ts26,

pro

AD

MP

44,

pro

ET

1P

44

P

CT

N/R

+

B

NP

27,

CR

PN

/R26,

Pro

AD

MP

44

P

or

S

-

Sy

mp

tom

sco

re (

at a

dm

issi

on

)28

Pro

AD

M

P

+

CR

PP

44,

PC

TN

/R44,

pro

ET

1P

44

Age,

Ch

arls

on’s

co

mo

rbid

ity s

core

, le

ft v

entr

icu

lar

ejec

tio

n

frac

tio

n44

Pro

ET

1

P

+

CR

PP

44,

PC

TN

/R44,P

roA

DM

P44

Age,

Ch

arls

on’s

co

mo

rbid

ity s

core

44

sIL

-1 R

II

P

+

∆le

uco

cyte

cou

nt9

Pag

e 50

of

58


SP

-D

S

-

Lu

ng f

un

ctio

n p

aram

eter

s46

sTN

F R

55

P

+

G

luco

seP (

on

Day

7)6

D

ieta

ry i

nta

ke/

RE

E r

atio

(on

Day

7)

P

+

Pro

tein

su

lfh

yd

ryl

con

cen

trat

ion

P45

T

EA

C

P

- S

up

ero

xid

e an

ion

rel

ease

by s

tim

ula

ted

neu

tro

ph

ils4

5

Co

mm

ents

:

a)T

he

stu

dy o

f H

urs

t et

al.

14co

mp

ared

36

pla

sma

bio

mar

ker

s at

EC

OP

D o

nse

t usi

ng a

mat

rix o

f 63

0 c

orr

elat

ion

s. I

n t

he

curr

ent

table

th

e m

ost

pro

min

ent

corr

elat

ion

s ar

e re

po

rted

.

b)

As

far

as p

red

icto

rs a

re c

on

cern

ed, in

a s

tep

wis

e m

ult

iple

lin

ear

regre

ssio

n m

od

el t

he

mo

st s

ign

ific

ant

pre

dic

tor

of

log l

epti

n a

nd

of

log a

dip

onec

tin

on

adm

issi

on

was

IL

6 w

her

eas

the

mo

st s

ign

ific

ant

pre

dic

tors

of

log L

/A r

atio

on

ad

mis

sio

n w

ere

TN

Fa

and

IL

617.

PC

T w

as a

pre

dic

tor

for

pro

AD

M44,

pro

ET

144

and

co

pep

tin

28 l

evel

s o

n a

dm

issi

on

. C

RP

lev

els

on

adm

issi

on

wer

e si

gn

ific

ant

pre

dic

tors

of

copep

tin

lev

els2

8.

Ab

bre

via

tio

ns:

BN

P:

bra

in n

atri

ure

tic

pep

tid

e, C

or.

: co

rrel

atio

n,

CR

P:

C-r

eact

ive

pro

tein

, E

CP

: eo

sin

op

hil

cat

ionic

pro

tein

, E

T-1

: en

do

thel

in 1

, E

PO

:

eryth

ropo

ieti

n,

FM

%:

fat

mas

s ex

pre

ssed

as

per

centa

ge

of

bo

dy w

eigh

t, F

EV

1:

forc

ed e

xp

irat

ory

vo

lum

e in

1se

c, G

SH

Px

: G

luta

thio

ne

per

ox

idas

e, I

gE

:

imm

un

oglo

bu

lin

E,

IGF

-I:

insu

lin

-lik

e gro

wth

fac

tor

I, I

L:

inte

rleu

kin

, IL

-1R

a: i

nte

rleu

kin

1 r

ecep

tor

anta

go

nis

t, I

P-1

0:

IFNγ

ind

uce

d p

rote

in 1

0, lo

g:

logar

ith

m,

MP

IF-1

: M

yel

oid

pro

gen

ito

r in

hib

itory

fac

tor-

1,

MP

O:

myel

op

erox

idas

e, P

:pla

sma,

PC

T:

pro

calc

ito

nin

, P

roA

DM

: pro

-ad

reno

med

ull

in,

Pro

ET

1:

pro

endo

thel

in 1

, R

EE

: re

stin

g e

ner

gy e

xp

end

iture

, S

: se

rum

, ,

SP

: sp

utu

m,

s T

NF

R:

solu

ble

tu

mo

r n

ecro

sis

fact

or

rece

pto

r, S

P-D

: su

rfac

tant

pro

tein

D,

TE

AC

: T

rolo

x e

quiv

alen

t an

tiox

idan

t ca

pac

ity,

TN

Fα

: tu

mo

r n

ecro

sis

fact

or α

, T

NT

: tr

op

onin

Sy

mb

ols

: +

: po

siti

ve

corr

elat

ion

, -:

neg

ativ

e co

rrel

atio

n, ∆

: ch

ange

du

rin

g t

he

cours

e of

EC

OP

D, ∆

(b-D

0):

chan

ge

bet

wee

n b

asel

ine

and

EC

OP

D o

nse

t, N

/R:

no

t re

port

ed

Pag

e 51

of

58


REFERENCES

1. Bathoorn E, Liesker JJ, Postma DS, et al. Change in inflammation in out-

patient COPD patients from stable phase to a subsequent exacerbation. Int J Chron

Obstruct Pulmon Dis 2009;4:101-9.

2. Bircan A, Gokirmak M, Kilic O, Ozturk O, Akkaya A. C-reactive protein

levels in patients with chronic obstructive pulmonary disease: role of infection. Med

Princ Pract 2008;17:202-8.

3. Bozinovski S, Hutchinson A, Thompson M, et al. Serum amyloid a is a

biomarker of acute exacerbations of chronic obstructive pulmonary disease. Am J

Respir Crit Care Med 2008;177:269-78.

4. Brekke PH, Omland T, Holmedal SH, Smith P, Soyseth V. Troponin T

elevation and long-term mortality after chronic obstructive pulmonary disease

exacerbation. Eur Respir J 2008;31:563-70.

5. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitonin-

guided treatment on antibiotic use and outcome in lower respiratory tract infections:

cluster-randomised, single-blinded intervention trial. Lancet 2004;363:600-7.

6. Creutzberg EC, Wouters EF, Vanderhoven-Augustin IM, Dentener MA,

Schols AM. Disturbances in leptin metabolism are related to energy imbalance during

acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care

Med 2000;162:1239-45.

7. Crooks SW, Bayley DL, Hill SL, Stockley RA. Bronchial inflammation in

acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur

Respir J 2000;15:274-80.

of 58


8. Daniels JM, Schoorl M, Snijders D, et al. Procalcitonin vs C-reactive protein

as predictive markers of response to antibiotic therapy in acute exacerbations of

COPD. Chest 2010;138:1108-15.

9. Dentener MA, Creutzberg EC, Schols AM, et al. Systemic anti-inflammatory

mediators in COPD: increase in soluble interleukin 1 receptor II during treatment of

exacerbations. Thorax 2001;56:721-6.

10. Dev D, Wallace E, Sankaran R, et al. Value of C-reactive protein

measurements in exacerbations of chronic obstructive pulmonary disease. Respir Med

1998;92:664-7.

11. Gompertz S, O'Brien C, Bayley DL, Hill SL, Stockley RA. Changes in

bronchial inflammation during acute exacerbations of chronic bronchitis. Eur Respir J

2001;17:1112-9.

12. Hill AT, Campbell EJ, Bayley DL, Hill SL, Stockley RA. Evidence for

excessive bronchial inflammation during an acute exacerbation of chronic obstructive

pulmonary disease in patients with alpha(1)-antitrypsin deficiency (PiZ). Am J Respir

Crit Care Med 1999;160:1968-75.

13. Hurst JR, Perera WR, Wilkinson TM, Donaldson GC, Wedzicha JA. Systemic

and upper and lower airway inflammation at exacerbation of chronic obstructive

pulmonary disease. Am J Respir Crit Care Med 2006;173:71-8.

14. Hurst JR, Donaldson GC, Perera WR, et al. Use of plasma biomarkers at

exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med

2006;174:867-74.

15. Kherad O, Kaiser L, Bridevaux PO, et al. Upper viral respiratory infection,

biomarkers and chronic obstructive pulmonary disease (COPD) exacerbations. Chest

2010;138:896-904.

of 58


16. Koutsokera A, Kiropoulos TS, Nikoulis DJ, et al. Clinical, functional and

biochemical changes during recovery from COPD exacerbations. Respir Med

2009;103:919-26.

17. Krommidas G, Kostikas K, Papatheodorou G, et al. Plasma leptin and

adiponectin in COPD exacerbations: Associations with inflammatory biomarkers.

Respir Med 2010;104:40-6.

18. Lazar Z, Huszar E, Kullmann T, et al. Adenosine triphosphate in exhaled

breath condensate of healthy subjects and patients with chronic obstructive pulmonary

disease. Inflamm Res 2008;57:367-73.

19. Perera WR, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery

and recurrence at COPD exacerbation. Eur Respir J 2007;29:527-34.

20. Phua J, Koay ES, Zhang D, et al. Soluble triggering receptor expressed on

myeloid cells-1 in acute respiratory infections. Eur Respir J 2006;28:695-702.

21. Quint JK, Donaldson GC, Goldring JJ, Baghai-Ravary R, Hurst JR, Wedzicha

JA. Serum IP-10 as a biomarker of human rhinovirus infection at exacerbation of

COPD. Chest 2010;137:812-22.

22. Sala E, Balaguer C, Villena C, et al. Low Erythropoietin Plasma Levels during

Exacerbations of COPD. Respiration 2010;80:190-7.

23. Sethi S, Wrona C, Eschberger K, Lobbins P, Cai X, Murphy TF. Inflammatory

profile of new bacterial strain exacerbations of chronic obstructive pulmonary disease.

Am J Respir Crit Care Med 2008;177:491-7.

24. Spruit MA, Gosselink R, Troosters T, et al. Muscle force during an acute

exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and

IGF-I. Thorax 2003;58:752-6.

of 58


25. Stockley RA, O'Brien C, Pye A, Hill SL. Relationship of sputum color to

nature and outpatient management of acute exacerbations of COPD. Chest

2000;117:1638-45.

26. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of

exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-

guidance with standard therapy. Chest 2007;131:9-19.

27. Stolz D, Breidthardt T, Christ-Crain M, et al. Use of B-Type Natriuretic

Peptide in the Risk Stratification of Acute Exacerbations of COPD. Chest

2008;133:1088-94.

28. Stolz D, Christ-Crain M, Morgenthaler NG, et al. Copeptin, C-reactive

protein, and procalcitonin as prognostic biomarkers in acute exacerbation of COPD.

Chest 2007;131:1058-67.

29. Tkacova R, Kluchova Z, Joppa P, Petrasova D, Molcanyiova A. Systemic

inflammation and systemic oxidative stress in patients with acute exacerbations of

COPD. Respir Med 2007;101:1670-6.

30. Weis N, Almdal T. C-reactive protein--can it be used as a marker of infection

in patients with exacerbation of chronic obstructive pulmonary disease? Eur J Intern

Med 2006;17:88-91.

31. Daubin C, Parienti JJ, Vabret A, et al. Procalcitonin levels in acute

exacerbation of COPD admitted in ICU: a prospective cohort study. BMC Infect Dis

2008;8:145.

32. Muller B, Morgenthaler N, Stolz D, et al. Circulating levels of copeptin, a

novel biomarker, in lower respiratory tract infections. Eur J Clin Invest 2007;37:145-

52.

of 58


33. Fiorini G, Crespi S, Rinaldi M, Oberti E, Vigorelli R, Palmieri G. Serum ECP

and MPO are increased during exacerbations of chronic bronchitis with airway

obstruction. Biomed Pharmacother 2000;54:274-8.

34. Rohde G, Gevaert P, Holtappels G, et al. Soluble interleukin-5 receptor alpha

is increased in acute exacerbation of chronic obstructive pulmonary disease. Int Arch

Allergy Immunol 2004;135:54-61.

35. Gerritsen WB, Asin J, Zanen P, van den Bosch JM, Haas FJ. Markers of

inflammation and oxidative stress in exacerbated chronic obstructive pulmonary

disease patients. Respir Med 2005;99:84-90.

36. Wedzicha JA, Seemungal TA, MacCallum PK, et al. Acute exacerbations of

chronic obstructive pulmonary disease are accompanied by elevations of plasma

fibrinogen and serum IL-6 levels. Thromb Haemost 2000;84:210-5.

37. Balbi B, Bason C, Balleari E, et al. Increased bronchoalveolar granulocytes

and granulocyte/macrophage colony-stimulating factor during exacerbations of

chronic bronchitis. Eur Respir J 1997;10:846-50.

38. Kythreotis P, Kokkini A, Avgeropoulou S, et al. Plasma leptin and insulin-like

growth factor I levels during acute exacerbations of chronic obstructive pulmonary

disease. BMC Pulm Med 2009;9:11.

39. Stankiewicz W, Dabrowski MP, Chcialowski A, Plusa T. Cellular and

cytokine immunoregulation in patients with chronic obstructive pulmonary disease

and bronchial asthma. Mediators Inflamm 2002;11:307-12.

40. Karadag F, Karul AB, Cildag O, Yilmaz M, Ozcan H. Biomarkers of systemic

inflammation in stable and exacerbation phases of COPD. Lung 2008;186:403-9.

of 58


41. Wilkinson TM, Hurst JR, Perera WR, Wilks M, Donaldson GC, Wedzicha JA.

Effect of interactions between lower airway bacterial and rhinoviral infection in

exacerbations of COPD. Chest 2006;129:317-24.

42. Calikoglu M, Sahin G, Unlu A, et al. Leptin and TNF-alpha levels in patients

with chronic obstructive pulmonary disease and their relationship to nutritional

parameters. Respiration 2004;71:45-50.

43. Noguera A, Busquets X, Sauleda J, Villaverde JM, MacNee W, Agusti AG.

Expression of adhesion molecules and G proteins in circulating neutrophils in chronic


44. Stolz D, Christ-Crain M, Morgenthaler NG, et al. Plasma pro-adrenomedullin

but not plasma pro-endothelin predicts survival in exacerbations of COPD. Chest

2008;134:263-72.

45. Rahman I, Skwarska E, MacNee W. Attenuation of oxidant/antioxidant

imbalance during treatment of exacerbations of chronic obstructive pulmonary

disease. Thorax 1997;52:565-8.

46. Shakoori TA, Sin DD, Ghafoor F, Bashir S, Bokhari SN. Serum surfactant

protein D during acute exacerbations of chronic obstructive pulmonary disease. Dis

Markers 2009;27:287-94.

47. Zeng M, Wen Y, Liu LY, Wang H, Guan KP, Huang X. Role of TNF-alpha,

sTNF-R55 and sTNF-R75 in Inflammation of Acute Exacerbations of Chronic

Obstructive Pulmonary Disease. Respiration 2009;78:399-403.

48. Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in

asthma, COPD, and smokers. Am J Respir Crit Care Med 1996;154:1055-60.

of 58


49. Gumral N, Naziroglu M, Ongel K, et al. Antioxidant enzymes and melatonin

levels in patients with bronchial asthma and chronic obstructive pulmonary disease

during stable and exacerbation periods. Cell Biochem Funct 2009;27:276-83.

50. Roland M, Bhowmik A, Sapsford RJ, et al. Sputum and plasma endothelin-1

levels in exacerbations of chronic obstructive pulmonary disease. Thorax 2001;56:30-

5.

51. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses,

symptoms, and inflammatory markers in acute exacerbations and stable chronic


52. Pinto-Plata VM, Livnat G, Girish M, et al. Systemic cytokines, clinical and

physiological changes in patients hospitalized for exacerbation of COPD. Chest

2007;131:37-43.

53. Brusse-Keizer MG, Grotenhuis AJ, Kerstjens HA, et al. Relation of sputum

colour to bacterial load in acute exacerbations of COPD. Respir Med 2009;103:601-6.

of 58


DOI 10.1378/chest.11-0495; Prepublished online August 11, 2011;Chest

Angela Koutsokera, Daiana Stolz, Stelios Loukides and Konstantinos KostikasCLINICAL CHALLENGE

SYSTEMIC BIOMARKERS IN EXACERBATIONS OF COPD: THE EVOLVING

November 14, 2011This information is current as of

http://chestjournal.chestpubs.org/content/early/2011/08/10/chest.11-0495Updated Information and services can be found at:

Updated Information & Services

http://www.chestpubs.org/site/misc/reprints.xhtmlonline at: Information about reproducing this article in parts (figures, tables) or in its entirety can be foundPermissions & Licensing

http://www.chestpubs.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:

Reprints

the right of the online article.Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to

Citation Alerts

slide format. See any online figure for directions. articles can be downloaded for teaching purposes in PowerPointCHESTFigures that appear in Images in PowerPoint format

[email protected]. For inquriires, please contact the AACP Media Relations Department at (847) 498-1400 or

Papers in Press are not under media or public embargo once the appear online.CHEST (DOI) and date of in-press publication. PubMed, but any references to an in-press article must include the digital object identifier version may contain substantive or nonsubstantive changes. These articles are indexed bypublished in an issue of the journal and have not yet been edited or typeset. The final

Papers in Press are peer-reviewed, accepted articles that have not yet beenCHEST


systemic biomarkers in exacerbations of copd: the evolving ... ex.pdf · of copd: the evolving...

Documents