(Chest. 2000;117:376S-379S.)
© 2000
American College of Chest Physicians
COPD*
Exacerbation
Norbert F. Voelkel, MD and
Rubin Tuder, MD
*
From the Division of Pulmonary Sciences and Critical Care Medicine and Department of Pathology, University of Colorado Health Sciences Center, Denver, CO.
Correspondence to: Norbert F. Voelkel, MD, Division of Pulmonary Sciences and Critical Care Medicine, 4200 E Ninth Ave, C272, Denver, CO 80262; e-mail: norbert.voelkel{at}uchsc.edu
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Abstract
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A renewed interest in the clinical and pathogenic aspects of COPD
exacerbation is timely in view of national and global COPD initiatives.
The three big problems regarding COPD continue to be the following:
prevention of the disease; slowing progression of the disease once
diagnosis has been established; and prevention and more
effective treatment of the so-called exacerbation. The following
assessment will raise more questions than answers and will review some
of the past and current concepts and contexts.
Key Words: COPD • definition • exacerbation
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Introduction
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Several
lung societies have provided practice guidelines and position
statements in an attempt to define COPD, to distinguish it from asthma,
and also to deal with an important aspect of COPD, namely, its
exacerbation.1
2
The word exacerbation has its root in the
Latin descriptive acerbus, meaning harsh, bitter, sharp, and
more at edge. Webster’s dictionary defines to exacerbate as "to make
more violent, more severe." This is where the problem with the phrase
"exacerbation of COPD" begins. Is it really more of the disease,
more of COPD, a harsher COPD, or is it something else, something
different from COPD? Surely, the acute exacerbation of COPD is not
respiratory failure due to pulmonary embolism, pneumothorax, or
pneumonia. But perhaps it is something else.
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Exacerbation of COPD: A Definition
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As stated, the exacerbation of COPD can, and often does, lead to
acute respiratory failure, but not every episode of respiratory failure
in COPD patients is caused by an exacerbation. The definitions of
"acute exacerbation" in several of the position papers are all a
bit different,1
2
indicating that there is no clear
understanding of the condition and no consensus among the experts. Yet,
it is very important that a generally accepted definition of COPD
exacerbation be agreed on and made available for clinical and
epidemiologic studies rather than have each investigator using his or
her own definition. The workshop conducted during this meeting is one
attempt in the effort to reach such a goal.
Intuitively, there must be a difference between mild or moderate
exacerbations and exacerbations that require treatment in an ICU. One
study found a hospital mortality rate of 24% if a patient with a COPD
exacerbation required ICU admission, and that mortality rate increased
to 30% if the patient was > 65 years.3
Earlier surveys
show different survival rates (Table 1
).4
5
6
7
Other factors, in addition to age, that are determining the survival of
patients with COPD exacerbation are severity of the lung disease and
extrapulmonary problems, such as ischemic heart disease, left
ventricular failure, and GI bleeding.8
Perhaps exacerbation of COPD is a syndrome characterized by a worsening
of dyspnea that exceeds the day-to-day variations in well-being and
dyspnea and that does not respond to treatment with a regular drug
regimen or to an increase in the dose of the conventionally used drugs.
Fatigue may be another component of the syndrome. A patient with a more
serious exacerbation may, in addition, present with tachycardia and
labored breathing. If this condition progresses, the patient then may
demonstrate evidence of respiratory failure with altered mental status
and a significant change in arterial blood gas levels from baseline
values. Such a graded scale syndrome differs from the criteria used by
Anthonisen et al,9
in which a type I exacerbation was
defined as increased sputum volume, or increased sputum purulence, or
increased dyspnea, and a type II exacerbation was defined as being
present when two of the above criteria were met.
The 1995 European Respiratory Consensus statement reads: "During
exacerbations, the clinical findings depend on the degree of additional
airflow limitation, the severity of underlying COPD and coexisting
conditions." It is clear that a patient with end-stage COPD and an
FEV1 of 0.41 at baseline may require very little
additional airflow limitation in order to experience an exacerbation.
How long does this additional airflow limitation have to exist before
it alters the clinical findings?
If exacerbation of COPD is a syndrome, then what factors cause the
syndrome, and what are the pathohistologic manifestations of the
syndrome?
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Cause of COPD Exacerbation
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Table 2
lists (not necessarily in a particular order) the most frequently cited
reasons or causes for COPD exacerbation. Numerous studies have been
conducted to investigate airway infections as etiologic factors
involved in COPD exacerbations. In 1969, Fisher et al10
investigated 56 exacerbations and found that significantly more
potentially pathogenic organisms (in particular, pneumococci and
Haemophilus influenzae) and viral and mycoplasmal organisms
were found in patients during exacerbations than in quiescent states. A
study by McHardy et al11
in 1980, conducted in Edinburgh
and London, found evidence for sputum eosinophilia in patients with
exacerbations. The authors stated that there was a clear tendency for
exacerbations to occur during the winter months, but a relationship
between their incidence and "changes in atmospheric pollution"
could not be established. Twelve percent of the cohort of patients
(presenting 77 exacerbations) had sputum isolates of H
influenzae, and 15% had isolates of Streptococcus
pneumoniae. Altogether, 30% of the patients with exacerbations
had specimens that were positive for bacterial isolates compared with
22% positive results in routine specimens.
Soler et al12
analyzed data on 50 patients with acute
exacerbations of COPD that required ventilator support. Four percent of
these patients had pneumonia and 72% had potentially pathogenic
organisms isolated in their tracheal aspirates, whereas, in 12% of
these patients no pathogen could be identified.
At present, there appears to be an agreement that the pathogens
isolated from the sputum during acute exacerbation are nontypable
H influenzae, S pneumoniae, and Moraxella
catarrhalis; however, these organisms also can be found
frequently in patients during the stable phases of COPD. This situation
is discussed extensively in Dr. Sanjay Sethi’s article in this
supplement.
During severe acute exacerbations in patients with severe COPD,
respiratory muscle fatigue, increases in dead space ventilation, and
(sometimes drug-induced) worsening of impaired ventilation-perfusion
matching can explain the worsening gas exchange and the deterioration
of the arterial blood gas levels.13
Whereas there
is a rather clear understanding regarding the deterioration of
physiologic parameters, there is an astonishing lack of published data
regarding the histopathologic features of the so-called acute
exacerbation of COPD. This is even more puzzling since patients do die
during such severe exacerbations. The lack of such histologic material
is illustrated in a handbook article14
in which a
schematic drawing was inserted in an attempt to illustrate the
pathohistologic findings because of the lack of available human
pathologic material. As a reminder, lung specimens obtained from
patients after death in status asthmaticus have been published for many
years. Figure 1 shows the lung histology obtained from a patient who had died because
of an exacerbation of COPD.
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Figure 1.. Top: a terminal bronchiole showing
the replacement of the mucosal lining by mucin-producing cells (arrow).
The lumen exhibits mucus admixed with scattered inflammatory cells and
desquamated epithelial cells. Focally, the mucosal layer shows basal
cell hyperplasia (hematoxylin-eosin, original x400).
Bottom: a respiratory bronchiole with evidence of
luminal accumulation of mucus admixed with desquamated cells and
inflammatory cells. Note the vascular congestion in the bronchiolar
wall (right corner), which is associated with cuffing by inflammatory
cells. The alveolar septa show vascular congestion and increased
numbers of acute inflammatory cells (arrows) (pentachrome, original
x400).
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Precisely because of the lack of a solid histologic database, it is
still uncertain whether the isolated pathogens are actually pathogenic
and what kind of lung and airway structure alterations they accomplish.
In very early autopsy studies, Jerzierski15
and, later,
Marchand16
described, examining autopsy specimens, a
pathogenetic process that they termed "bronchiolitis exudativa,"
and Mitchell et al,17
again studying autopsy specimens,
identified a bronchiolitis in approximately 26% of the patients who
had evidence of chronic airway obstruction.
Vascular congestion of the airway mucosa and plasma
exudation18
19
triggered by
inflammation20
21
22
could be another pathologic
mechanism that can quickly narrow the already severely altered
small airway geometry. Similarly, the rapid development of goblet cell
hyperplasia23
and mucus hypersecretion24
into
the small airway lumen could produce nonbronchospastic flow
limitation.
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Markers of Acute COPD Exacerbation
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Given the critical condition of patients with severe exacerbation
of COPD, one can understand that there are few data on BAL fluid
available. Selby et al25
examined the first-pass
neutrophil retention in lung tissue, comparing patients with COPD who
were in stable condition with patients who had acute
exacerbations.5
They found an increase in the retention of
neutrophils during exacerbations. The levels of isoprostanes have been
found to be increased in the BAL fluid in patients with interstitial
lung diseases.26
Pratico et al27
reported
increased urinary excretion of the isoprostane
F2
-III in hypoxemic patients with acute
exacerbations. This increase in the urinary excretion of isoprostane
F2-III was reversed after treatment and
improvement in oxygenation of these patients. In patients with
exacerbations that were associated with airway infections, but also in
those without evidence of bacterial pathogens, an increase in plasma
C-reactive protein and subsequent normalization with effective
treatment has been reported.28
Whether or not airway inflammation is a sine qua non for
acute exacerbations is not known but, at present, is assumed. If so,
the development of a noninvasive test that would utilize exhaled air
samples for the analysis of inflammation-related markers would be of
clinical importance.
Perhaps the term "inflammation" should be redefined to become
more inclusive. For example, there is increasing evidence that hypoxia
increases the gene expression of inflammatory mediators in monocytes
and macrophages. If so, perhaps hypoxia is part of the inflammation
paradigm, and, consequently, long-term oxygen treatment might have
beneficial effects because of its inhibition of inflammatory
activities.
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COPD Is Not Asthma
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Since COPD and asthma are different, despite some overlap,
the treatment guidelines so valuable in the management of patients with
asthma may not be applicable to COPD patients, and the recommendations
for the treatment of COPD exacerbations may not be translated from
asthma treatment guidelines. The treatment recommendation certainly
depends on the severity of the exacerbation. Empirically, patients with
acute respiratory failure require invasive or noninvasive respiratory
support and the consensus statement provided by the European
Respiratory Society is, therefore, rather general, recommending that
"the main goals of hospital management of an exacerbation of COPD are
to evaluate the severity, including life threatening conditions, to
identify the cause of the exacerbation, to provide controlled
oxygenation and to return the patient to the best previous
condition." The American Thoracic Society recommendations for the
treatment of a severe exacerbation are the following: "... to
increase the dosage of ß2-agonists, to increase
the ipratropium dosage, to administer IV theophylline, to administer IV
steroids and to treat the patient with antibiotics if so indicated."
The situation regarding treatment of COPD and COPD exacerbations can
perhaps best be summarized with the following quotation: "Despite the
enormous advances in understanding the pathophysiology of
asthma and the development of new drugs, there has been
little advance in our understanding of the molecular and cellular
mechanisms involved in COPD and there has been little progress in drug
development."29
The three major treatment modalities of
COPD exacerbations apparently remain antibiotics,9
ß-receptor agonists,30
and steroids.31
32
33
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TOP
Abstract
Introduction
