An Updated Definition and Severity Classification of COPD Exacerbations: The Rome Proposal

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An Updated Definition and Severity Classification of COPD
Exacerbations: The Rome Proposal
Bartolome R. Celli, MD*1, Leonardo M. Fabbri, MD*,2,&, Shawn D. Aaron, MD3,
Alvar Agusti, MD, PhD4, Robert Brook, MD5, Gerard J. Criner, MD6,&,
Frits M.E. Franssen, MD, PhD,7,8, Marc Humbert, MD, PhD9,10, John R. Hurst, PhD11, Denis
O’Donnell, MD12, Leonardo Pantoni, MD, PhD13, Alberto Papi, MD14, Roberto Rodriguez-
Roisin, MD, PhD15, Sanjay Sethi, MD16, Antoni Torres, MD, PhD17, Claus F. Vogelmeier, MD18,
and Jadwiga A. Wedzicha, MD19,+
*These authors contributed similarly to the formulation and conduct of this work
Affiliations
1. Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital. Professor of
Medicine. Harvard Medical School, Boston, MA, USA
2. Section of Respiratory Medicine, Translational Medicine & Romagna, University of Ferrara,
Ferrara, Italy
3. The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada
4. Cátedra Salud Respiratoria, University of Barcelona; Respiratory Institute, Hospital Clinic,
IDIBAPS, CIBERES, Barcelona, Spain
5. Wayne State University, Detroit, MI, USA
6. Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple
University, Philadelphia, PA, USA
7. Department of Research and Education, CIRO, Horn, The Netherlands.
AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

Copyright © 2021 by the American Thoracic Society
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8. Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, the
Netherlands.
9. Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance
Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
10. Université Paris-Saclay, INSERM UMR_S 999, Le Kremlin-Bicêtre, France
11. UCL Respiratory, University College London, London, UK
12. Respiratory Investigation Unit, Queens University and Kingston Health Sciences Centre,
Kingston, Ontario, Canada
13. “Luigi Sacco” Department of Biomedical and Clinical Sciences, University of Milan, Milan,
Italy
14. Respiratory Medicine, University of Ferrara; Emergency Department, University Hospital S.
Anna, Ferrara, Italy
15. University of Barcelona, Hospital Clinic-IDIBAPS, CIBERES, Barcelona, Spain
16. Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo,
NY, USA
17. Department of Pulmonology, Hospital Clinic, Universitat de Barcelona, IDIBAPS, Icrea
academia, Ciber de Enfermedades Respiratorias, Barcelona, Spain
18. Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre
Giessen and Marburg, Philipps-University Marburg, Member of the German Centre for Lung
Research (DZL), Marburg, Germany
19. Respiratory Division, National Heart and Lung Institute, Imperial College, London UK
+ Editor in Chief, AJRCCM (participation complies with American Thoracic Society
requirements for recusal from review and decisions for authored works).

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& Associate Editor, AJRCCM (participation complies with American Thoracic Society
requirements for recusal from review and decisions for authored works).
Corresponding author
Bartolome R. Celli
31 River Glen Rd
Wellesley, MA 02481
USA
Tel: 617-678-0177
e-mail: bcelli@copdnet.org
Authors’ contributions
BC and LMF developed the original concept for this work, including the organization of the
Delphi methodology upon which the content is based. All authors contributed to the Delphi
surveys, to the literature searches and the virtual discussions. The first draft of the manuscript
was written by BC, with all authors then providing intellectual input. All authors approved the
final version.
Funding
This work was funded by Chiesi Farmaceutici SpA.
Running header
COPD Exacerbations – The Rome Proposal
Descriptor number: 9.7 COPD: Exacerbations
Word count: 3362 words

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This article has an online data supplement, which is accessible from this issue's table of contents
online at www.atsjournals.org.
This article is open access and distributed under the terms of the Creative Commons Attribution
Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-
nd/4.0/). For commercial usage and reprints please contact Diane Gern (dgern@thoracic.org).

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AT A GLANCE COMMENTARY
Scientific knowledge on the subject: Precise and practical definitions for acute medical events
are needed if clinicians are to effectively diagnose and manage patients, provide prognostic
information, and implement precision medicine. The current definition of a chronic obstructive
pulmonary disease exacerbation (ECOPD) is subjective and based solely on worsening of
respiratory symptoms. Further, severity is classified post hoc by the healthcare resource used to
treat the event. These shortcomings support the need to revise the ECOPD definition.
What this study adds to the field: The Rome proposal for an updated definition of ECOPD
addresses many of the shortcomings of older definitions. Based on extensive literature review
and using Delphi methodology, it specifies the timespan within which worsening of symptoms
define an ECOPD. Second, to the subjective worsening of symptoms it adds a series of clinical
variables that are objectively measurable and readily available: dyspnea, oxygen saturation,
respiratory rate, heart rate, C-reactive protein and, if needed, arterial blood gases. Third, based on
agreed thresholds, it integrates these variables into three mutually exclusive severity categories
that can be used to classify the exacerbation severity at initial patient contact. This proposal aims
to facilitate and improve clinical care, research, and health services planning.

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ABSTRACT
The current definition of a chronic obstructive pulmonary disease (COPD) exacerbation
(ECOPD) is based solely on worsening respiratory symptoms, with severity classified post hoc
by the healthcare resource used to treat the event, which may vary among practitioners and
healthcare systems. These shortcomings support a need to revise the ECOPD definition and
severity classification to one that is useful at time of patient contact. To achieve this, an expert
panel used a modified Delphi method of five rounds of questions generated by a thorough review
of the literature, supplemented by virtual discussions. For the 80 identified questions, the
agreement level was rated using a Likert scale from 0 (strongly disagree) to 9 (strongly agree).
Consensus was defined a priori as a median score ≥7 (strong agreement). The proposed
definition states: “In a patient with COPD, an exacerbation is an event characterized by dyspnea
and/or cough and sputum that worsens over ≤14 days, that may be accompanied by tachypnea
and/or tachycardia, often associated with increased local and systemic inflammation caused by
airway infection, pollution, or other insult to the airways.” Three severity categories (mild,
moderate, or severe) were defined using integration of six clinically measurable variables:
intensity of dyspnea, oxygen saturation, respiratory rate, heart rate, C-reactive protein, and, if
indicated, arterial blood gases. In conclusion, by incorporating measurable clinical and
laboratory variables at the time of exacerbation, the Rome proposal for an updated definition of
ECOPD could help standardize care and outcomes for clinicians and researchers alike.
Abstract word count: 246 words
Keywords: chronic bronchitis; smoking; respiratory failure; symptom flare up; breathlessness

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Over 200 years ago, René Laennec published the first description of emphysema, an
important pathobiological element of what is today known as chronic obstructive pulmonary
disease (COPD) (1). He stated that the disease was characterized by persistent dyspnea
punctuated by acute episodes of worsening, frequently associated with newly developed and/or
worsening cough and sputum (labeled as “acute catarrh”) that could lead to “suffocation”. These
episodes have subsequently been termed exacerbations of COPD (ECOPD) (2, 3). Over 150
years later, Anthonisen et al (4) provided a definition, similar to Laennec’s, that has remained
relatively unchanged over the last 35 years, and forms the basis of the European Respiratory
Society/American Thoracic Society definition: “In a patient with underlying COPD,
exacerbations are episodes of increasing respiratory symptoms, particularly dyspnea, cough and
sputum production, and increased sputum purulence” (5). A slightly modified definition has
been used primarily in the research field: “A sustained worsening of the patient’s condition from
the stable state and beyond normal day-to-day variations, necessitating a change in regular
medication in a patient with underlying COPD” (6), similar to that in the Global Initiative for
Chronic Obstructive Lung Disease (GOLD) strategy document, which reads: “An acute
worsening of respiratory symptoms that results in additional therapy” (7). GOLD then classifies
ECOPD severity as mild when only symptoms are reported and the patient is treated with inhaled
short-acting bronchodilators, moderate when the patient receives antibiotics, systemic
corticosteroids or both, and severe when the patient visits an emergency room or is hospitalized
due to the event (6, 7). Without denying the therapeutic progress made in the prevention of
ECOPD (5–8), treatment of the episodes per se has remained relatively unchanged (5, 7, 9).

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Shortcomings of the current ECOPD definition
The current definition of ECOPD has several shortcomings that adversely affect clinical
and healthcare decisions (Supplementary Table 1). First, it relies exclusively on a patient’s
subjective perception of increased respiratory symptoms, which varies from patient to patient
(10) and can be mimicked and/or aggravated by other conditions such as pneumonia, cardiac
events or pulmonary embolism (6, 7, 11, 12). Second, it does not relate the symptoms to
measurable pathophysiological variables that could characterize the event itself. Third, it lacks a
framework for timing of the event’s evolution, an element that can help differentiate ECOPD
from other processes with similar symptoms. Finally, severity is established post hoc by the
healthcare resource used to treat the event (13, 14), with this subjectivity introducing variability
due to differences between practitioners and healthcare systems. A novel approach is therefore
needed because precise, practical and objective point-of-care definitions and severity
assessments for acute medical events are needed by clinicians and researchers if they are to
effectively diagnose them at the point of contact, assess prognosis, and implement precision
treatment (15). All of these shortcomings could be overcome by integrating knowledge gathered
from observational and interventional studies, as well as with the help of currently available
technology capable of measuring in real time the clinical and laboratory variables that can serve
as surrogate markers of event severity.
Scope of this perspective
This perspective proposes an updated definition and severity classification of ECOPD
based on the principles outlined by Scadding for the taxonomy of diseases (16), integrating
symptoms, function, and surrogate markers of the process underlying ECOPD. It intends to be

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objective, practical and useful to clinicians and researchers alike. In its development, the authors
acknowledge that episodes of worsening of respiratory symptoms similar to ECOPD may occur
in patients with chronic diseases other than COPD, and these potential causes should be
considered in the differential diagnosis of the event (7, 17). The process itself was initiated and
coordinated by BC and LMF aided by a medical writer (DY) who identified experts with
international recognition that have conducted research and published on the definition, diagnosis,
pathobiology and/or treatment of ECOPD as well as similar events in closely related fields. A
modified Delphi method (18, 19) was considered the most appropriate scientific tool to achieve
the desired goals because: a) it is a valid method to obtain consensus based on informed
opinions; b) it provides a structured mechanism to maintain a fluid communication process,
allowing individuals to deal with a complex problem; c) the issue in question does not lend itself
to precise analytical techniques, but can benefit from subjective judgments on a collective basis;
and d) the method is based on anonymous responses to the selected items, so decreasing the
chance that the dominant personality of one or more of the participants may drive the final
conclusions.
Due to the SARS-Cov-2 pandemic, an initial face-to-face meeting to be held in January
2020 in Rome, Italy (hence the name of this proposal) was replaced with a virtual meeting to
define the project. Given the need to maintain continuous interaction and as suggested by Delphi
methodologists (18, 19), a target panel size of 15–20 experts was agreed upon, and of the 19
members contacted 17 accepted (Supplementary Table 2). The method consisted of sequential
rounds of questions, each followed by virtual meetings with open discussion of results (modified
Delphi), aimed at facilitating consensus building. Details of the one-year process, the 80 items
evaluated and Delphi references are included in the supplement (Supplementary Figure 1, Tables

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3–7, and text). The results and the different drafts of the manuscript were circulated to the
panelists, all of whom contributed to this perspective.
The ECOPD conceptual model and proposed definition
Current evidence indicates that an ECOPD is characterized by an acute burst of airway
inflammation due to bacteria, viruses, environmental pollutants or other stimuli (Figure 1) (2–4,
20–28). This has been documented by carefully conducted studies in the outpatient and inpatient
setting (21, 29), with many studies showing that the inflammatory process may expand
systemically (29). This inflammatory burst, coupled with worsening of the existing airflow
limitation, increases the work of breathing in patients with limited respiratory reserve. A vicious
cycle of increased airways resistance and tachypnea leads to gas trapping in the lungs,
respiratory muscle dysfunction, worsening dyspnea, and ventilation-perfusion mismatch
manifesting as arterial hypoxemia with or without hypercapnia (30–35). In some patients,
ventilatory demand exceeds reserve, leading to ventilatory insufficiency, hypercapnia and
respiratory acidosis that, if untreated, may cause death (34).
Based on this conceptual model, the panel agreed to propose the following definition: “In
a patient with COPD, an exacerbation is an event characterized by dyspnea and/or cough and
sputum that worsens over ≤14 days, that may be accompanied by tachypnea and/or tachycardia,
often associated with increased local and systemic inflammation caused by airway infection,
pollution, or other insult to the airways.” These events can be life-threatening and require
adequate evaluation and treatment.

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Timing of ECOPD
A review of the literature provides reasonable support of a timeframe for exacerbations to
develop. Indeed, a study of 4439 exacerbations showed that the time from first onset of
worsening respiratory symptoms to a full ECOPD ranged from 0–5 days in 90% of patients, with
an overall range of 0–14 days (36). This is similar to an observational study that, using diary
cards, described prodromal symptoms over 4–7 days, with lung function then decreasing
abruptly on the day of documentation of the ECOPD (37). Importantly, subjects with COPD
experimentally infected with rhinovirus develop upper respiratory symptoms 2–3 days following
the inoculation, with lower respiratory symptoms and breathlessness peaking 4–10 days after
infection (38). These observations helped reach a consensus that the upper time limit for an
ECOPD to develop is 14 days from first onset of symptom worsening, and that in some cases
ECOPD may develop over just hours. The timing of resolution of exacerbations is less well
established. In a study of 101 patients observed over 2.5 years, median recovery times from onset
of ECOPD were 6 days (interquartile range [IQR] 1 to 14) for peak expiratory flow (PEF) and 7
days (IQR 4 to 14) for daily total symptom score (37). Recovery of PEF to baseline values
occurred in only 75.2% of ECOPD by 35 days and 92.9% of ECOPD by 91 days. In a small
proportion of patients, PEF values or symptoms never returned to normal, an observation similar
to that of another study of 145 patients (39). The use of objective variables readily measurable to
determine severity, as proposed in this perspective, could improve knowledge about the time of
resolution, a much needed metric to compare effectiveness of therapies.

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Grading the severity of ECOPD
The current grading of the severity of an ECOPD, based on post-facto utilization of
healthcare resources, is a major limitation of the current definition. Due to global variability in
the available resources to treat patients and local customs affecting the criteria for hospital visits
and admissions, there is substantial variability in ECOPD reported outcomes (13, 40). This is of
particular importance in the interpretation of results of interventional studies and in the planning
of future clinical trials (13). To address this limitation, the panelists propose three mutually
exclusive severity categories (mild, moderate, and severe) integrating six objectively measured
variables that serve as markers of event severity: dyspnea, oxygen saturation, respiratory rate,
heart rate, serum C-reactive protein (CRP) and, in selected cases, arterial blood gases (Table 1).
These variables were consensually agreed upon from a potential list of 21 that were the subject
of a thorough literature review and discussion. Of these potential variables, the worsening of
cough and sputum deserved special attention. Cough and sputum increase or color change can
occur during ECOPD and, in a proportion of cases, may be the most relevant symptom or sign
(20); however their intensity has not been properly measured, making it difficult to include them
in ECOPD severity classification. However, while cough and sputum remain an integral part of
the ECOPD definition, the panelists agreed that worsening dyspnea is the most relevant symptom
for most patients, and because it is measurable it is useful when grading the episode severity.
Measurable variables useful to grade the severity of ECOPD
Dyspnea
In COPD clinical studies, dyspnea changes over time have been measured using several
scales, including diary cards (36, 37), the Transitional Dyspnea Index (41) and the

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EXAcerbations of Chronic pulmonary disease Tool (EXACT-PRO) (42). However, most patients
with COPD do not routinely quantify their daily dyspnea intensity. Consensus was reached to
recommend the visual analog scale (VAS), which has been validated against ventilatory loads
(43), can be represented by a numerical scale from 0 (no shortness of breath) to 10 (maximal
shortness of breath ever experienced) (43), and has a minimally clinical important difference
(MCID) of 1 (44). Resting VAS dyspnea values range from 0–3 in patients with COPD (10, 43,
45), whereas when measured in the emergency ward or in the hospital values are higher than 4
(30, 35, 46). Experts agreed that a visual analog scale (VAS) score ≥5 (on a scale of 0 to 10) in
the context of a suspected ECOPD indicates severe dyspnea. This pragmatic approach removes
the need to consider a change in dyspnea from a previous baseline VAS value.
Respiratory and heart rate
Studies have shown that both heart rate and respiratory rate increase in the days
preceding, during and following ECOPD (30, 31, 47, 48), and are measurable by widely
available noninvasive methods offering a window to the severity of the episodes (48–51).
Resting heart rate increases with COPD severity, and is associated with mortality risk (52),
regardless of etiology or medication use. Heart rates >85 bpm or increases in heart rates by 10–
15 bpm compared to baseline were reported during an acute exacerbation (49). Respiratory rates
>24 breaths per min, with shortened expiratory time leading to gas trapping, have been
consistently reported in most studies conducted in hospitalized patients (51, 53), whereas
respiratory rates of 18–20 breaths per min were documented in patients receiving outpatient care
(53). The panel reached consensus that a heart rate <95 bpm and a respiratory rate <24 breaths
per min could help separate mild from moderate ECOPD.

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Hypoxemia and hypercapnia
Ventilation-perfusion (VA/Q) imbalance is the most important mechanism responsible
for the gas exchange abnormalities in COPD (32, 33). Given that stable COPD can be associated
with arterial hypoxemia with or without hypercapnia, both absolute measurements and a change
in values would be useful as determinants of severity. Assessment of blood gases is ideal, but it
is not available in all clinical settings, whereas pulse oximetry is practical and widely available,
although we acknowledge that it may be less accurate in Black patients (7). It is known that
decompensated hypercapnic respiratory failure is associated with increased mortality (34), which
is reduced by non-invasive ventilation (NIV) (34, 54). While expert societies recommend
titrating supplemental oxygen during ECOPD to SaO2 of 88–92% (7, 55), studies of ECOPD
suggest the average reduction in SaO2 was not more than 2% (56, 57). Based on this evidence,
the panel agreed that when change from baseline is known, a mild ECOPD would be
characterized by an arterial oxygen saturation (SaO2) ≥92% and a change ≤3%, a moderate event
would be SaO2 <92% and/or a change >3%, and a severe event by acidotic hypercapnic
respiratory failure, i.e., arterial partial pressure of carbon dioxide (PaCO2) >45 mmHg and pH
<7.35.
Serum C-reactive protein
Healthy subjects, smokers without COPD, and patients with stable COPD usually have
CRP values <10 mg/L (58, 59), with higher values within this range associated with increased
risk of hospitalization and death (60, 61). Serum CRP levels increase in both viral and bacterial
ECOPD (25, 26), although they are usually higher in the latter (22, 26) which is why values may
be used at point-of-care to guide antibiotic therapy (26, 62). In outpatients with COPD who are

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suffering an ECOPD, CRP levels increase modestly from basal values (23, 63). In patients in the
emergency ward or admitted to hospital, higher CRP values have been reported, ranging from 8–
156 mg/L (63–65). Although the panel acknowledged the lack of specificity of serum CRP as a
marker of airway or lung inflammation, consensus was reached that a CRP value ≥10 mg/L can
help separate mild from moderate ECOPD. We do not assign CRP a weight any different from
HR, RR or oxygen saturation. A patient could have a more severe episode defined exclusively by
a combination of the clinical signs without a CRP >10 mg/L. Our proposal aims to help push the
inclusion of at least one measurable point of care marker, the threshold of which can be amended
over time, if this proposal is implemented and the results so suggest.
Integration of the variables in a practical severity classification scale
The panelists agreed that integration of the five easy to evaluate parameters (dyspnea,
respiratory rate, heart rate, oxygen saturation and serum CRP) be used to assess the severity of an
ECOPD, both in the clinical evaluation of patients and in research and clinical trials (Table 1,
Figure 2). The default severity classification is that of a mild event. For an episode to be
considered moderate, at least three of these five parameters, all of which carry a similar weight,
should be worse than those threshold values characteristic of mild ECOPD. The panelists also
agreed that for an ECOPD to be considered severe, a sixth variable, arterial blood gas values,
must indicate the presence of hypercapnia (PaCO2 >45 mmHg) and respiratory acidosis (pH
<7.35).
Other important tests
The panelists reviewed 16 other clinical and laboratory tests used in the diagnosis and
severity classification of ECOPD (Supplementary Tables 3 and 4). Of these, several require

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some comments. Routine spirometry or any lung function assessment cannot be reliably obtained
during an ECOPD as patients are usually too sick to perform an adequate spirometry maneuver,
changes from baseline are often small, and pre-ECOPD results may not be available. Panelists
also thought that efforts made to develop accurate devices that can help monitor lung function
over time would provide a major advance in our capacity to integrate this variable to future
improvements on this proposal. Peripheral blood eosinophils would have potential use for
therapeutic guidance, particularly regarding the use of systemic steroids (66), but eosinophil
levels have not been used for ECOPD diagnosis or severity classification. The chest
roentgenogram is useful to differentiate pneumonia (and other conditions that may mimic
ECOPD such as pneumothorax or pleurisy) from an ECOPD (67), and it is frequently obtained in
patients seen in healthcare facilities, but this tool has not been used to define or classify the
severity of an ECOPD.
Confounding morbidities
A review of the literature revealed at least 28 conditions that may clinically mimic an
ECOPD (Supplementary Table 5) and the panelists reached strong consensus that three deserved
special consideration (heart failure, pneumonia and pulmonary embolism) (7, 17, 31, 67–71), not
only because of their frequency but also because they require specific and prompt management
to improve outcome. The panel acknowledged that these conditions may coexist with ECOPD
and influence the evolution of each other. As summarized in Table 1 and Figure 2, a thorough
clinical evaluation is often adequate to exclude these conditions; however, further diagnostic
testing such as additional imaging studies and biomarker measurements may be required.
Acknowledging the difficulty in separating events as the single or main cause of clinical
decompensation in some patients, or their synchronic occurrence, it should be possible in most

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healthcare settings to establish a correct diagnosis. Other comorbid conditions did not receive
consensual agreement or disagreement but deserve some comments; five (pneumothorax, acute
anxiety, asthma attack, myocardial infarction, and arrythmias) were felt to have specific clinical,
radiological and laboratory characteristics that facilitate their diagnosis. For the remaining
potential confounders, the panelists thought their inclusion was of lesser importance (i.e., strong
disagreement over their inclusion) and should only be considered in rare circumstances. A
practical approach to patients with symptoms consistent with an ECOPD is summarized in
Figure 2. The Rome proposal for an updated definition and severity classification of ECOPD will
not preclude a more precise approach based on treatable traits in future studies (72).
Limitations of this proposal
The panelists acknowledge that there are some limitations to this proposal. First, the
present document was drafted by experts from North America and Western Europe. This choice
was influenced by the SARS-Cov-2 pandemic, and the need to host discussions by
videoconference, which would have made discussions difficult across discordant time zones. The
inclusion of experts from eight countries and six main specialties does provide some confidence
about the wide scope of the panelists’ expertise. In addition, the validation of the elements
contained in this proposal is open for everyone to test. Second, the number of participants
selected may seem arbitrary, however it is within the optimal number recommended by experts
in the methodology of the Delphi process, allowing for ample discussion during the virtual
meetings (see the text in the supplement). Third, the selection of the thresholds for the different
variables included in the severity classification and for the timing of the ECOPD may seem
arbitrary and not based on prospectively validated studies. However, they were agreed upon by
anonymous consensus after review of the available literature and intense discussion between

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rounds (Supplementary Table 6), significant features of the Delphi methodology. Of note, in this
era of technological devices, continuous accurate monitoring of measurable variables may better
help detect onset of an event and its resolution over time, facilitating not only the evaluation of
novel therapies, but the implementation of early interventions before the event progresses.
Conclusions
The Rome proposal for an updated definition and severity classification of ECOPD was
drafted by an international panel of experts, using a framework that focused on feasibility and
potential validity. The consensus was reached using a modified Delphi methodology, informed
by data from studies reporting objective measurements of symptoms, signs, physiological
variables and biomarkers. The predictive value of the variables classifying the severity was
assessed using the potential intensity of care needed for treatment and stabilization of the patient.
This revised definition addresses many of the shortcomings of the current definition and should
better inform clinical care, research, and health services planning, but needs to be validated
prospectively in adequately designed and powered studies.
Acknowledgements
Writing support (in the form of editing content for grammar and journal style) was provided by
David Young of Young Medical Communications and Consulting Ltd. This support was funded
by Chiesi Farmaceutici SpA.

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Figure legends
Figure 1. Causes, pathobiological mechanisms and pathophysiological consequences in an
exacerbation of COPD (7, 35).
COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein.
Figure 2. Diagnostic approach to a patient suspected of an exacerbation of COPD.
*Dyspnea (using a visual analog scale), respiratory rate, heart rate, oxygen saturation (absolute
and/or change), and C-reactive protein.
COPD, chronic obstructive pulmonary disease; RR, respiratory rate; HR, heart rate; SaO2,
arterial oxygen saturation; CRP, C-reactive protein; ABG, arterial blood gas; PaCO2, partial
pressure of carbon dioxide.

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Tables
Table 1. The Rome proposal for an updated definition and severity classification of COPD
exacerbations.
In a patient with COPD, an exacerbation is an event characterized by dyspnea and/or cough and
sputum that worsens over ≤14 days, that may be accompanied by tachypnea and/or tachycardia,
often associated with increased local and systemic inflammation caused by airway infection,
pollution, or other insult to the airways.
Diagnostic approach
1) These events can be life-threatening and require adequate evaluation and treatment.
2) Complete a thorough clinical assessment for evidence of COPD and potential respiratory and non-
respiratory concomitant diseases, including consideration of alternative causes for the patient’s
symptoms and signs; primarily pneumonia, heart failure and pulmonary embolism.
3) Assess:
a) Symptoms; severity of dyspnea using VAS, and document presence of cough;
b) Signs (tachypnea, tachycardia), sputum volume and color, and respiratory distress (accessory
muscle use).
4) Evaluate severity using appropriate additional investigations such as: pulse oximetry, laboratory
assessment, CRP and/or arterial blood gases.
5) Establish cause of the event (virus, bacterial, environmental, other)
COPD, chronic obstructive pulmonary disease; VAS, visual analog scale; CRP, C-reactive protein.

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Figure 1. Causes, pathobiological mechanisms and pathophysiological consequences in an exacerbation of

COPD
338x190mm (300 x 300 DPI)

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Figure 2. Diagnostic approach to a patient suspected of an exacerbation of COPD.*Dyspnea (using a visual

analog scale), respiratory rate, heart rate, oxygen saturation (absolute and/or change), and C-reactive
protein.
189x219mm (300 x 300 DPI)

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An Updated Definition and Severity Classification of COPD
Exacerbations: The Rome Proposal
Bartolome R. Celli, Leonardo M. Fabbri, Shawn D. Aaron, Alvar Agusti, Robert Brook, Gerard J.
Criner, Frits M.E. Franssen, Marc Humbert, John R. Hurst, Denis O’Donnell, Leonardo Pantoni,
Alberto Papi, Roberto Rodriguez-Roisin, Sanjay Sethi, Antoni Torres, Claus F. Vogelmeier, and
Jadwiga A. Wedzicha
Supplement

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Supplementary Table 1. Shortcomings in the current definition of exacerbation in patients with

COPD and how they have been addressed in this revision.
Current definition (1–4) Addressed in the updated

Rome definition
Timing Not specified Acute time specified
Mechanism Not specified Symptoms and function

specified
Severity classification Post-hoc based-on Thresholds of clinical variables

healthcare resource utilization defined at point of contact to
be used in the clinical and
research environments
Differential diagnosis Minimally addressed Most important considerations

to be considered specified in the definition

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Supplementary Table 2. Characteristics of the expert panelists participating in the project.
Specialty Number
Pulmonologists 12
Cardiologist 1
Critical care medicine 1
General internist 1
Neurologist 1
Pulmonary vascular disease 1
Experience in the field of COPD exacerbations
>20 years 15
10–20 years 2
Country
United States 4
Spain 3
Italy 3
United Kingdom 2
Canada 2
France 1
Germany 1
The Netherlands 1

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Detailed description of the modified Delphi method
Background
The Delphi method aims to reach consensus among a group of experts in the context of
anonymity and with little influence by the dominant personalities that tend to drive face to face
meetings. The optimal number of panelists members in the Delphi methodology is not fixed, and
does not have to be large. Several methodological papers reviewing the topic state that the
number may be as low as three and as high as 80 (5–7).
What is stressed is the need to recruit experts on the topic, and to guarantee
participation with as few dropouts as possible, something that our panel excelled in, with 100%
participation over the five rounds and one year of the study. Previous statements in the medical
field using the Delphi method had a number of panelists very similar to ours. For example, the
Third International Consensus Definitions for Sepsis and Septic Shock included 19 panelists (8),
a panel that developed recommendations for a treatment algorithm in pulmonary sarcoidosis
included 26 experts (9), and consensus recommendations on dosing and administration of
medical cannabis to treat chronic pain were based on a Delphi process with 20 experts (10).
Consistent with the vast majority of the Delphi consensus documents and statements
published in the literature (8–10), participants in our Delphi panel were all from western Europe
and north America (Supplementary Table 2). Indeed, in the last American Thoracic Society
statement on pharmacotherapy of COPD all of the participants were from the USA, Canada,
UK, Germany and Switzerland (11). Indeed our panel included experts from a wider range of
countries than in any of the consensus documents cited above.

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We acknowledge that our panel did not include any primary care physicians. For a
definition and rational approach to the definition and severity classification of ECOPD, we (the
organizers) felt it would be best to gather experts on ECOPD together with specialists in related
diseases, and experts in ECOPD differential diagnosis.
Modified Delphi Method implemented in this perspective
The first round of questions was formulated by the chairs, followed by a thorough
discussion of results and expansion of the process to identify gaps and items arising by the
interaction among the experts (Supplementary Figure 1). The following items were agreed upon:
timing and importance of symptoms, incorporation of biomarkers, classification of severity, and
the confounding effect of other diseases. This resulted in an initial set of 22 statements on the
definition requiring three rounds (Supplementary Table 3), a subsequent set of two rounds to
review 21 statements on severity classification (Supplementary Table 4), and 28 statements on
potential confounding conditions (Supplementary Table 5). To classify ECOPD severity, five
working groups were assigned to review the literature and provide potential exacerbation
severity threshold values for practical and clinically measurable variables. These underwent the
same Delphi methodology by the whole group, to consensually agree on the threshold values
that were integrated into a working classification to grade severity of the episode
(Supplementary Table 6). A final statement on nomenclature of the severity (Supplementary
Table 7) increased the total number of items included in the exercise to 80. Throughout the
process, panelists were blinded to each other’s responses and rated their degree of consensus
using a 9-point Likert scale ranging from 0 (strongly disagree) to 9 (strongly agree). Consensus
was defined a priori with a median Likert score ≥7 (strong agreement) or ≤3 (strong
disagreement), with the interquartile range (IQR) describing the variance amongst responders.
Virtual meetings following each round allowed ongoing respondent discussion, a strategy useful
in the Modified version of Delphi studies to help reinforce consensus (12–14).

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Supplementary Figure 1. Outline of the modified Delphi consensus process used in generating
the proposed Rome Consensus Definition of COPD exacerbations.

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Supplementary Table 3. Panel of questions addressing the need and variables to be included
in an updated definition of COPD exacerbations. Green color identifies the items that reached
consensual agreement.
Median IQR
Objective of the exercise
1 There is a need for an updated definition of a COPD exacerbation 8.5 0.5
Subjective variables
2 Dyspnea is the dominant symptom signaling an exacerbation 8 1
3 Dyspnea measurement should be an integral part of the updated definition 8 3

of exacerbations
4 Quantification of dyspnea with a visual analog or Borg scale is useful in 7 3

grading dyspnea during exacerbations
5 Sputum should be included in an updated definition of a COPD 7 2

exacerbation
6 Cough should be included in an updated definition of a COPD exacerbation 7 3
Objective variables
7 Respiratory rate should be part of an updated definition of a COPD 6 5

exacerbation
8 Heart rate should be part of an updated definition of a COPD exacerbation 5 5
9 Temperature should be part of an updated definition of a COPD 4 4

exacerbation
10 Oxygen saturation should be part of an updated definition of a COPD 6 6

exacerbation
Supportive laboratory variables
11 Arterial blood gases should be part of an updated definition of a COPD 4 4

exacerbation
12 Peak expiratory flow should be part of an updated definition of a COPD 4 3

exacerbation
13 Spirometry should be part of an updated definition of a COPD exacerbation 4 4
14 White blood cell count should be part of an updated definition of a COPD 4 4

exacerbation

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Median IQR
15 Blood eosinophils should be part of an updated definition of a COPD 5 5

exacerbation
16 C-reactive protein should be a marker included in an updated definition of 6 4

COPD exacerbation
17 Blood levels of NT-proBNP should be included to differentiate chronic heart 6 4

failure from COPD exacerbations
18 Troponin levels should be included to differentiate myocardial infarction from 6 4

COPD exacerbations
19 A level of D-Dimer should be included in an updated definition of a COPD 5 5

exacerbation
20 A sputum culture should be part of a definition of a COPD exacerbation 4 2
21 A chest roentgenogram should be part of an updated definition of a COPD 6 6

exacerbation
22 There is a need to develop a classification of the severity of a COPD 8 1

exacerbation
23 The definition of exacerbations of COPD should include the statement “It is 7 4

caused by an acute burst of the airways, lung, and systemic inflammation
that characterizes COPD”

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Supplementary Table 4. Panel of questions addressing the potential components to classify

the severity of an exacerbation of COPD. Green color identifies the items that reached
consensual agreement.
Median IQR
Symptoms
24 Quantification of dyspnea (visual analog or Borg scale) is an important 8 2

component of the assessment of severity of exacerbation
25 The new onset or worsening of sputum is an important component of the 6 2

assessment of severity of exacerbations
26 The increase of volume in sputum is an important component of the 6 2

assessment of severity of exacerbations
27 The purulence of sputum is an important component of the assessment of 6 3

the severity of exacerbations
28 The presence of cough is an important component of the assessment of the 6 2

severity of exacerbations
Vital signs
29 Quantification of respiratory rate is an important component of the 8 2

assessment of the severity of exacerbations
30 Quantification of heart rate is an important component of the assessment of 7 2

the severity of exacerbations
31 Quantification of temperature is an important component of the assessment 5 3

of the severity of exacerbations
32 Quantification of O2 saturation is an important component of the 9 1

Supportive laboratory variables
33 Arterial blood gases are an important component of the assessment of the 8 3

34 Quantification of peak expiratory flow is an important component of the 6 2

35 Quantification of spirometry is an important component of the severity of 5 2

exacerbations
36 Quantification of white blood cells is an important component of the severity 5 2

of exacerbations

Page 43 of 49
Median IQR
37 Quantification of blood eosinophils is an important component of the 4 3

38 Quantification of procalcitonin is an important component of the severity of 6 3

exacerbations
39 Quantification of C-reactive protein is an important component of the 7 2

40 Quantification of NT-proBNP is an important component of the severity of 6 3

exacerbations
41 Quantification of troponin is an important component of the severity of 6 3

exacerbations
42 Quantification of D-dimer is an important component of the severity of 5 4

exacerbations
43 Characterization of sputum culture is an important component of the 4 3

44 The outcomes of a chest X-ray is an important component of the severity of 5 4

exacerbations

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Supplementary Table 5. Panel of questions addressing the potential acute illnesses to be

considered in the differential diagnosis of COPD exacerbations. Green color identifies the items
that reached consensual agreement. Yellow color identifies the items with consensual
disagreement on the statement. White background identifies items with no consensus.
Condition Median IQR
45 Abscess hypopharynx 1 2
46 Acute vocal cord paralysis 1 3
47 Acute bronchorrhea in bronchiectasis 4 4
48 Acute asthma attack 6 3
49 Tracheobronchomalacia 3 4
50 Intraluminal tumors 3 3
51 Lung abscess 2 1
52 Foreign body/mucous plugs 2 3
53 Acute interstitial pneumonitis 3 4
54 Lobar pneumonia 7 3
55 Pleural effusion 5 3
56 Exacerbation of pulmonary fibrosis 4 3
57 Pneumothorax 6 5
58 Pulmonary embolism 7 4
59 Anemia 4 4
60 Arrhythmia 5.5 3
61 Constrictive pericarditis 2 3
62 Pericardial effusion 2 4
63 Myocardial infarction 6 3
64 Heart failure 8 2
65 Metabolic acidosis 3 4
66 Valvular rupture in the heart 2 2

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Condition Median IQR
67 Acute Guillain-Barré syndrome 1 1
68 Diaphragmatic paralysis 2 2
69 Thyroid storm 0 2
70 Anxiety/panic attack 6 3
71 Somatiform disorder 3 4
72 Delirium 3 4

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Supplementary Table 6. Panel of questions to define the threshold values useful to separate
mild from moderate severity exacerbations.
Threshold value questions Median IQR
The maximum period for worsening of symptoms to be considered a

73 7 4
COPD exacerbation is 14 days
A dyspnea threshold value of <5 cm in a VAS that ranges from 0 (no

74 dyspnea) to 10 cm (most dyspnea ever felt) can help differentiate a 8 2
lesser from a more severe degree of severity of a COPD exacerbation
A respiratory rate threshold value of <24 breaths per min can help
75 differentiate a lesser from a more severe degree of severity of a COPD 8 1
exacerbation
A heart rate threshold value of <95 bpm can help differentiate a lesser
76 7 2
from a more severe degree of severity of a COPD exacerbation
An oxygen saturation threshold value of SaO2 >92% breathing ambient

77 air AND a change in SaO2 <3% (when known) can help differentiate a 8 1
lesser from a more severe degree of severity of a COPD exacerbation
A CRP threshold value of <10 mg/L can help differentiate a lesser from a
78 7 2
more severe degree of severity of a COPD exacerbation.
Integration of the variables
When applied in clinical research to define the severity of an

79 exacerbation, rank the following three statements in order of preference,
where 1 = most preferred, and 3 = least preferred.
First choice 5
A numerical integration of all five variables is needed to define the
A Second choice 5
severity of an exacerbation.
Third choice 8
First choice 2
A numerical integration of four of the five variables is needed to define
B Second choice 10
the severity of an exacerbation.
Third choice 3
First choice 8
A numerical integration of three of the five variables is needed to define
C Second choice 2
the severity of an exacerbation.
Third choice 5

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Supplementary Table 7. Nomenclature for severity of COPD exacerbations.
Nomenclature
Which of the following three severity nomenclatures would you choose to

80
define exacerbation severity? Please, only select one.
A Unstable COPD, exacerbation, ventilatory failure 1 vote
B Mild exacerbation, moderate exacerbation, severe exacerbation 8 votes
Less severe exacerbation, severe exacerbation, very severe

C 7 votes
exacerbation
There was 1 abstention.

Page 48 of 49
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An Updated Definition and Severity Classification of COPD Exacerbations: The Rome Proposal

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An Updated Definition and Severity Classification of COPD

Exacerbations: The Rome Proposal

Bartolome R. Celli, MD*1, Leonardo M. Fabbri, MD*,2,&, Shawn D. Aaron, MD3,

and Jadwiga A. Wedzicha, MD19,+

Medicine. Harvard Medical School, Boston, MA, USA

2. Section of Respiratory Medicine, Translational Medicine & Romagna, University of Ferrara,

3. The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada

4. Cátedra Salud Respiratoria, University of Barcelona; Respiratory Institute, Hospital Clinic,

IDIBAPS, CIBERES, Barcelona, Spain

5. Wayne State University, Detroit, MI, USA

University, Philadelphia, PA, USA

7. Department of Research and Education, CIRO, Horn, The Netherlands.

AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

8. Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, the

9. Department of Respiratory and Intensive Care Medicine, Hôpital Bicêtre, Assistance

Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France

10. Université Paris-Saclay, INSERM UMR_S 999, Le Kremlin-Bicêtre, France

11. UCL Respiratory, University College London, London, UK

Kingston, Ontario, Canada

14. Respiratory Medicine, University of Ferrara; Emergency Department, University Hospital S.

Anna, Ferrara, Italy

15. University of Barcelona, Hospital Clinic-IDIBAPS, CIBERES, Barcelona, Spain

17. Department of Pulmonology, Hospital Clinic, Universitat de Barcelona, IDIBAPS, Icrea

academia, Ciber de Enfermedades Respiratorias, Barcelona, Spain

Research (DZL), Marburg, Germany

+ Editor in Chief, AJRCCM (participation complies with American Thoracic Society

AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

This work was funded by Chiesi Farmaceutici SpA.

COPD Exacerbations – The Rome Proposal

Descriptor number: 9.7 COPD: Exacerbations

Word count: 3362 words

AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-

AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

pulmonary disease exacerbation (ECOPD) is subjective and based solely on worsening of

AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

The current definition of a chronic obstructive pulmonary disease (COPD) exacerbation

indicated, arterial blood gases. In conclusion, by incorporating measurable clinical and

Abstract word count: 246 words

AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

important pathobiological element of what is today known as chronic obstructive pulmonary

Society/American Thoracic Society definition: “In a patient with underlying COPD,

short-acting bronchodilators, moderate when the patient receives antibiotics, systemic

AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

Shortcomings of the current ECOPD definition

as surrogate markers of event severity.

Scope of this perspective

This perspective proposes an updated definition and severity classification of ECOPD

AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

opinions; b) it provides a structured mechanism to maintain a fluid communication process,

Due to the SARS-Cov-2 pandemic, an initial face-to-face meeting to be held in January

AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

panelists, all of whom contributed to this perspective.

The ECOPD conceptual model and proposed definition

Current evidence indicates that an ECOPD is characterized by an acute burst of airway

respiratory muscle dysfunction, worsening dyspnea, and ventilation-perfusion mismatch

manifesting as arterial hypoxemia with or without hypercapnia (30–35). In some patients,

ventilatory demand exceeds reserve, leading to ventilatory insufficiency, hypercapnia and

respiratory acidosis that, if untreated, may cause death (34).

adequate evaluation and treatment.

AJRCCM Articles in Press. Published September 27, 2021 as 10.1164/rccm.202108-1819PP

A review of the literature provides reasonable support of a timeframe for exacerbations to

Bartolome R. Celli, MD1, Leonardo M. Fabbri, MD,2,&, Shawn D. Aaron, MD3,