Chest Surg Clin N Am

13 (2003) 615 – 629

Medical management of chronic obstructive

pulmonary disease
Frank C. Sciurba, MD
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh,
1211 Kaufmann Building, Pittsburgh, PA 15213, USA

Chronic obstructive pulmonary disease (COPD) has recently been a major focus
of research offering hope for therapeutic advances. This effort is in part energized
by the recognition that approximately 24 million adults in the United States have
evidence of impaired lung function and experience 9.5 million office and emer-
gency room visits, 726,000 hospitalizations, and 119,000 deaths each year [1].
While the death rate finally appears to be stabilizing in the United States at this
unacceptable rate, the problem is still escalating worldwide [2]. Factors that impair
more rapid progress in COPD treatment include misconceptions that the disease is
irreversible and untreatable, lack of consensus on optimal functional outcome
parameters, and incomplete understanding of appropriate short-term surrogate
markers representing disease-modifying activity of new agents that might take
years to manifest their anatomic, physiologic, and clinical effects.

Diagnosis and assessment

COPD should be suspected in all individuals who have an environmental
exposure history (eg, tobacco) or who have persistent symptoms of cough, sputum
production, or dyspnea. Routine physical examination has limited value in
diagnosing early disease because wheezing during tidal breathing is more common
with asthma or during exacerbation. One less conventional physical examination
maneuver, a ‘‘forced expiratory time’’ maneuver, can increase the sensitivity of
diagnosing air flow obstruction in an office setting. For this maneuver patients are
asked to take a deep breath and breathe out forcibly for as long as they can, as with a

E-mail address: sciurbafc@upmc.edu

1052-3359/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved.
doi:10.1016/S1052-3359(03)00099-1
616 F.C. Sciurba / Chest Surg Clin N Am 13 (2003) 615–629

spirometry effort, and the clinician auscultates at the trachea to ascertain the
presence of air flow. A forced expiratory time greater than 6 seconds improves the
sensitivity of diagnosing air flow obstruction, and a value greater than 10 seconds is
90% specific, albeit only 40% sensitive for air flow obstruction [3,4].

Spirometry
Spirometry screening should be performed to confirm the diagnosis in anyone
who has risk factors for COPD. The recent Global Initiative for Chronic Obstruc-
tive Pulmonary Disease [5] guidelines define air flow obstruction simply by the
spirometric ratio of forced expiratory volume in 1 second to forced vital capacity
(FEV1/FVC) of less than 0.7. Because this ratio decreases normally with aging, the
American Thoracic Society defines disease based on age-related predicted values.
Using such a standard, values for a 30-year-old patient of less than 0.74 are
abnormal, whereas for an octogenarian a ratio above 0.68 would be considered to
be normal [6]. In asymptomatic smokers over the age of 45 years, 9% of men and
14% of women will have spirometric evidence of air flow obstruction. The
prevalence of obstruction increases to more than 25% in symptomatic smokers
[1,7]. Other testing can be useful in further defining disease subtype or to rule out
secondary processes.

Measurements of lung volume

Lung volume measurements might be useful in ruling out a combined restrictive
process. The total lung capacity and residual volume should be increased in COPD
because of decreased lung elastic recoil and early closure of airways resulting in
hyperinflation. Accurate determinations of lung volumes require body plethys-
mography (body box) measurements as gas dilution and washout techniques
underestimate the volume of trapped air. Measurements of lung volumes before
and after bronchodilator therapy might identify bronchodilator responders who do
not show reversibility using spirometric measures, although this is rarely per-
formed in clinical practice [8,9].

Diffusing capacity
Diffusing capacity measurements correlate most closely with the amount of
radiographic emphysema and tend to be more normal in airway-dominant air flow
obstruction. Single breath diffusing capacity for carbon monoxide is useful in
identifying patients who require further exercise testing to rule out exertional
desaturation. Patients who had values of greater than 55% predicted in one series
never experienced exercise-associated desaturation, whereas values of less than
55% predicted were associated with further exercise desaturation in approximately
half of patients [10].
 F.C. Sciurba / Chest Surg Clin N Am 13 (2003) 615–629 617

Arterial blood gases

Arterial blood gases should be measured at rest in all patients who have an FEV1
less than 40% predicted, patients who have disproportionate symptoms at rest or
with exertion, and in patients who have cor pulmonale. Arterial PO2 values less
than 60 mmHg indicate the need for further consideration of supplemental oxygen.
Arterial PCO2 values of greater than 50 mmHg indicate acute or chronic respira-
tory failure. In a chronic setting, increased PCO2 disproportionate to the degree of
airway obstruction might be an indicator of associated obstructive sleep apnea.

Exercise testing
The role of exercise testing in the evaluation of COPD is evolving. Patients who
have diffusing capacity measurements less than 55% predicted or who have
disproportionate exertional dyspnea should have oximetry measurements obtained
during exertion [10]. The type of exercise can range from hall walking to more
formal treadmill and exercise protocols. More formal cardiopulmonary exercise
testing might be useful in sorting out the relative contributions of simultaneous
cardiovascular or pulmonary vascular comorbidities to exercise intolerance [11].
Recent reports also suggest that exercise testing is a better predictor of disease
prognosis than more conventional parameters [12,13].

Imaging
A chest radiograph should be ordered to rule out other cardiac or pulmonary
comorbidities and to aid in differential diagnosis. Plain chest radiographs can be
useful in ruling out bronchiectasis or giant bullous disease or in determining the
extent and distribution of emphysema. CT can be useful in assessing the airway
thickening and dilation associated with bronchiectasis or the regional hyperinfla-
tion on expiratory imaging associated with obliterative bronchiolitis, which might
be included in the differential diagnosis of air flow obstruction. Furthermore, given
the potential for improved survival in the appropriate subgroup of patients
following lung volume reduction surgery, CT scanning should be considered in
all patients who have an FEV1 less than 45% predicted who would consider
undergoing surgery.

a-1 antitrypsin
Patients who have COPD who are less than 45 years old and who have a
significant family history of emphysema or patients who have lower lobe dominant
disease should have serum levels of a-1 antitrypsin measured or genotyping
performed for the abnormal ZZ or SZ genotype. Identification of the deficiency is
most important in identifying the increased risk to the individual or their family
members. To date there in only modest evidence that intravenous augmentation
therapy is effective in patients who have moderate pulmonary impairment [14].
618 F.C. Sciurba / Chest Surg Clin N Am 13 (2003) 615–629

Prevention

Smoking cessation
Assessment of smoking exposure and subsequent smoking cessation interven-
tion are the only proven disease-modifying interventions in COPD patients [15].
The five ‘‘As’’ outlined by the United States Public Health Service offers an
approach for the clinician [16]:
Ask—Devise a system that assesses the smoking status of each patient seen in
the office. Incorporation of smoking status as the fifth vital sign during triage can
serve this purpose.
Advise—Educate every smoker on the risks of smoking and strongly and
personally advise them to quit.
Assess—Determine the willingness to quit at this time.
Assist—Provide personal counseling. A strong physician message can in itself
result in a 5% quit rate. Consider referring to a formal smoking cessation program
for more formal social support programs. Organizational support such as that
offered through the American Cancer Society or American Lung Association is
also effective, although availability differs regionally.
Pharmaceutical intervention is effective, and clinicians should maintain a low
threshold for intervention with nicotine replacement therapy (NRT) or Bupro-
pion therapy. Both agents can improve long-term quit rates. No form of NRT
(eg, transdermal patch, gum, inhaler, nasal spray, lozenge) has proven to be more
effective than another form. Bupropion, an antidepressant that enhances central
noradrenergic activity, has been shown to increase the 12-month quit rate to 30%
versus 16% with NRT alone. A common regimen for Bupropion administra-
tion is to start 1 to 2 weeks before the quit date, use the sustained release
preparation at 150 mg/d for 4 days then increase to 150 mg twice daily if
tolerated. Maintenance dosing is recommended for less than 6 months following
cessation. The most significant side effect associated with Bupropion is seizures,
although this effect is uncommon in individuals who do not have a prior sei-
zure condition.
Arrange—When an effective intervention has been established, it is critical to
arrange for follow-up care. It is important to recognize that tobacco dependency is
often a relapsing condition that might require ongoing intervention. A clinician
would not begin antihypertensive therapy and neglect follow-up until 6 months
later. Short-term follow-up delivers the message to the patient that they are
undergoing an important medical intervention, and it enhances the chance of
compliance with therapy.

Other environmental
While cigarette exposure is the dominant cause of COPD, other occupational
and environmental exposures clearly contribute to the development of the disease,
particularly in genetically susceptible individuals. While coal and cadmium
 F.C. Sciurba / Chest Surg Clin N Am 13 (2003) 615–629 619

exposures have proven independent effects from tobacco smoke alone, it can be
difficult in small series to separate the impact of tobacco from many other
potentially causative industrial exposures. It is also likely that outdoor air pollution
and indoor exposure to combustion products of home heating fuels contribute
significantly in some regions [17].

Influenza vaccination
Influenza vaccination should be given yearly to all patients who have COPD and
has been proven to decrease serious morbidity or death [18]. Pneumococcal
vaccine is recommended, although definitive data regarding its effectiveness are
not available [5].

Pharmaceutical management

Bronchodilators
Bronchodilator therapy remains central to the management of COPD and has
been proven to improve FEV1, dyspnea, quality of life, and exercise capacity
[19 – 22]. The acute improvement in expiratory flow rates, such as FEV1 fol-
lowing bronchodilator, is, on average, greater in asthma patients than in COPD
patients (16% versus 11%, respectively); however, despite the common use of
bronchodilator reversibility in the clinical and research setting to distinguish
asthma from COPD, there is significant prevalence of bronchodilator reversibility
in patients who have COPD [23,24]. Twenty-seven percent of patients who have a
known genetic predisposition to COPD who were enrolled in the National Heart,
Lung, and Blood Institute a-1-antitrypsin deficiency registry had significant bron-
chodilator reversibility.
There is, however, also rationale for using bronchodilator therapy in patients
who do not demonstrate acute spirometric FEV1 reversibility in the laboratory. The
change in resting and dynamic lung hyperinflation following bronchodilator
treatment appears to have clinical relevance independent of changes in expiratory
flow measurements such as FEV1 in COPD patients. The impact of lung
hyperinflation on symptoms and impairment at rest and during exertion is
increasingly recognized in COPD [9,25,26]. The consequences of hyperinflation
include a shortened diaphragm with less efficient neuromechanical coupling and
constraints on inspiratory reserve volume, resulting in dyspnea. A study in patients
who had moderate to severe COPD who did not exhibit reversibility in expiratory
flow parameters revealed that 83% of these patients had significant improvements
in lung volume indices [27]. Furthermore, patients who had the most severe disease
exhibited the greatest absolute improvements. It is likely that the ‘‘pharmaceutical
volume reduction’’ present in COPD and asthma patients is not an incidental
finding of secondary importance to changes in expiratory flow rates but rather the
dominant response to therapy.
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The reporting of ‘‘mean’’ bronchodilator responses in clinical trials can obscure

clinically important variability among individual patients or distinguishable sub-
groups. For example, in one recent trial [28] the average improvement in FEV1 was
significantly better in the bronchodilator group compared with the placebo group;
however, assessment of the distribution of responses revealed that 18% of subjects
in the treatment group had 0% or less improvement, and even more subjects had
less than a 15% improvement despite statistically significant improvements in
FEV1 in the group as a whole. A significant fraction had larger than mean
improvements. Such subgroup analysis or the distribution of responses is per-
formed rarely [29,30].
Of the classes of bronchodilators,,, b agonists, anticholinergics, and phospho-
diesterase inhibitors (theophylline preparations), no consistent difference in
effectiveness has been found, although phosphodiesterase inhibitors are relegated
to second- or third-line use because of a greater side effects profile. It is likely that
individual patients differ with respect to their ability to respond to individual or
combination therapy. Patients who remain symptomatic should be offered sequen-
tial alternate or combination therapy in an attempt to optimize benefit.

Long- versus short-acting inhaled bronchodilator therapy

The greatest recent advances in bronchodilator therapy are the development and
approval of long-acting bronchodilators. Currently, two long-acting b agonist
preparations (Salmeterol and Formoterol) have been approved and one long-acting
anticholinergic (Tiotropium) is pending final U.S. Food and Drug Administration
(FDA) approval. Long-acting preparations provide similar peak FEV1 effects as
short-acting preparations yet produce greater duration of benefit and higher trough
FEV1 values, and in most trials they have induced changes in dyspnea, quality of
life, and exacerbation frequency [19 – 21,31,32]. Few studies address the impact of
longer-acting bronchodilators on lung volume parameters reflecting improvements
in lung hyperinflation [33,34]. Salmeterol and Formoterol have durations of action
of 12 hours and are delivered on a twice-daily basis. Tiotropium has a 24-hour
duration and is delivered once daily. Cardiac side effect profiles in the approved
dosing ranges have not differed from placebo and there has been no evidence of
tachyphylaxis with these preparations [35].

Theophylline
Theophylline was reviewed in a 1985 article, and its controversy continues [36].
While the bronchodilator effects and symptomatic improvements of theophylline
are not debated, the side effect profile and drug –drug interactions have prohibited
consideration of theophylline as a first-line agent. Current recommendations to
maintain levels in the 5 to 12 mcg/mL range allow significant bronchodilator
synergy with inhaled preparations while minimizing the side effect profile.
Theophylline should be considered as an acceptable second- or third-line therapy
in patients who remain symptomatic after optimizing other inhaler therapy.
 F.C. Sciurba / Chest Surg Clin N Am 13 (2003) 615–629 621

Combination therapy
The combination of b-adrenergic, anticholinergic, and theophylline prepara-
tions might provide benefit to more patients who respond disproportionately to one
of the agents, and there is evidence that synergy might also occur between agents.
Preliminary abstracts suggest additive benefits of long-acting b agonists and
Tiotropium. Other reports combining long-acting b agonists with short-acting
anticholinergic agents confirm additive therapeutic effects [37,38]. Theophylline
has also been shown to have significant additive benefit when combined with
Salmeterol [39,40]. The combination of long-acting b agonists with inhaled
corticosteroids has also shown promise in COPD patients [41,42].

Corticosteroids
Systemic steroids. Systemic glucocorticoids are important in the management of
acute exacerbation; however, long-term usage results in a dose-dependent decrease
in long-term survival [43]. Tapering patients off steroids following exacerbation is
often difficult given the short-term pulmonary effects and psychological effects of
such therapy; however, it is clear that the long-term consequences, including
myopathy, osteopenia, and immunosuppression, warrant a vigilant approach.
Inhaled corticosteroids have gained increasing acceptance in the management
of COPD.

Inhaled corticosteroids. The international expert panel [5] has recommended that
inhaled corticosteroids (ICS) be considered for patients who have a low FEV1 and
repeated exacerbations, or for symptomatic patients who respond to a 6- to 12-week
trial of ICS. A superficial analysis of the literature could lead to a rejection of such
therapy, but a closer examination of the whole body of literature supports the
recommendations of the expert panel [44]. To date there have been five large,
multicenter trials evaluating the use of ICS in the treatment of COPD: the Lung
Health Study (LHS) [45], Inhaled Steroid in Obstructive Lung Disease (ISOLDE),
[46], European Respiratory Society Study on Chronic Obstructive Pulmonary
Disease (EUROSCOP) [47], Copenhagen [48], and the International COPD Study
Group (ICSG) trial [49]. Four trials revealed no change in the rate of decline in
FEV1 over 2 to 4 years as their primary outcome parameters, and the fifth, ICSG,
revealed no change in the number of subjects having an exacerbation at 6 months of
follow-up care.
A critical review of methodology used in ICS trials offers critical insights into
the assessment of clinical trials in COPD.

Disease severity. The disease severity in these trials was not representative of
the population at greatest risk, which is most commonly seen by the clinician.
Several of the trials studied subjects largely from screened smoking populations,
whose relatively mild disease (Copenhagen, FEV1 86% predicted; EUROSCOP,
77% predicted; LHS, 64% predicted) was not representative of the most desperate
subjects, having an FEV1 of less than 50% predicted. Thus, only ISOLDE (FEV1
622 F.C. Sciurba / Chest Surg Clin N Am 13 (2003) 615–629

57% predicted) and ICSG (FEV1 50% predicted) are somewhat relevant for the
more severe subjects.

Entry and exclusion criteria. Entry and exclusion criteria restrict generalizability
to other subclasses of patients. ISOLDE and ICSG restricted entry of subjects who
had mild bronchodilator reversibility but no history of asthma, whereas LHS did
not restrict entry of reversible or airway hyperresponsive subjects. ICSG chose
subjects who had a history of exacerbation, thus creating a cohort significantly
different in character than the other trials, which had a smaller proportion of
subjects who had a history of repeated exacerbation, but possibly more similar to
the subjects who were frequent users of the health care system.

Outcome measures. The choice of outcome measures impacted conclusions.

Secondary analyses revealed a 25% decrease in total exacerbations in the ISOLDE
study and a significant slowing of the rate of decline of the Saint George quality of
life questionnaire. ICSG, which looked at frequency of exacerbation as a primary
outcome, was not powered sufficiently for a 6-month trial to confirm this effect, but
it did show in this short period a significant shift in the severity of exacerbations
from moderate and severe to mild (outpatient treated) episodes.

Other factors. Several other decisions in trial design might have resulted in an
underestimation of the ICS treatment effect in the ISOLDE trial. Firstly, 60% of
subjects screened for the trial had been on ICS and had undergone washout
before entry. Thirty-eight percent of those individuals experienced an exacerba-
tion, in contrast to 6% of subjects in the ICS naı̈ve washout group. Twenty-four
percent of subjects were withdrawn from randomization consideration during this
washout phase and likely represented an important subgroup of patients who
could not tolerate withdrawal of ICS [50]. Finally, the dropout rate from the
placebo arm exceeded the dropout rate in the ICS arm (25% versus 19%). There
was no attempt to collect follow-up (intent-to-treat analysis) data on subjects
returning to ICS in the placebo group, which might have resulted in an upward
drift in lung function in this group.
The reduced exacerbation frequency seen with ICS use might be responsible for
the findings from population-based cohort studies, which suggest reduced hospi-
talization frequency or even mortality benefits of ICS [51,52], but the merits of
such nonrandomized study designs have been debated [53].

Other pharmaceutical therapy

Mucolytics
While the role for mucolytic agents in COPD has been controversial, a recent
systematic review of the literature identified a 29% reduction in exacerbation rate
and greater reduction in total days of illness in patients treated with a variety of
mucolytic agents, even though there was no difference in pulmonary function
 F.C. Sciurba / Chest Surg Clin N Am 13 (2003) 615–629 623

between the groups. Some of these agents, including N-acetylcysteine, might also
have beneficial antioxidant properties. While these results suggest that a new focus
on parameters other than FEV1 might be necessary to prove efficacy of these drugs,
further clinical trials are necessary before recommending widespread usage of
these old or emerging therapies [54].

Psychoactive medications
There is a high frequency of depression and anxiety associated with COPD,
hence a high degree of suspicion should be maintained for associated depression or
anxiety disorders. Antidepressants should be administered using the same criteria
to treat depression in the general population. Anxiolytics and narcotics, while
possibly beneficial in selected patients, should be used cautiously because of
associated serious adverse effects, especially in patients who have more advanced
disease [55,56]. Recent reports on Buspirone, a nonbenzodiazepine anxiolytic,
demonstrated improved anxiety, exercise tolerance, and dyspnea at doses of 20 mg
daily, although the widespread applicability of this treatment has not been
confirmed [57].

Unproven therapies
To date there are no data in COPD populations documenting effectiveness of
leukotriene modifying agents, which are used widely in asthma patients. Pulmo-
nary vasodilator therapies should also be used cautiously, if at all, because of
potential worsening ventilation – perfusion imbalance and deterioration in gas
exchange [58].

Emerging therapies
Current research is underway in various phases evaluating drugs that modulate
inflammatory response in the lungs, increase antioxidant defenses, alter protease –
antiprotease balance, influence lung repair and remodeling responses, influence
inhaled xenobiotic metabolism, improve oxygen carrying capacity, and influence
peripheral muscle function [59].

Nonpharmaceutical management

Oxygen therapy
The use of supplemental oxygen therapy is now widely accepted based on the
results of two large clinical trials documenting a survival benefit in hypoxemic
subjects [60,61]. The entry criteria for these trials now constitute the basis for
insurance reimbursement (ie, arterial PO2  55 mmHg or PO2 55 –60 in the
presence of cor pulmonale or polycythemia). Emerging evidence suggests,
however, that decreased ventilation requirements resulting in improved dyspnea
624 F.C. Sciurba / Chest Surg Clin N Am 13 (2003) 615–629

and exercise endurance can be found in nonhypoxemic patients given supplemental

oxygen therapy [62].

Pulmonary rehabilitation
The stated goals of pulmonary rehabilitation are to reduce symptoms, improve
quality of life, and increase physical and emotional participation in everyday
activities [5]. While a comprehensive pulmonary rehabilitation program should
include education, optimization of compliance with medical care, and appropriate
psychological and nutritional counseling, the dominant component of intervention
is upper and lower extremity strength and endurance exercise training [63,64].
Pulmonary rehabilitation programs are not uniformly available because of regional
differences in insurance reimbursement. Among the reasons cited for lack of
support of pulmonary rehabilitation programs include the lack of proven mainte-
nance programs to sustain benefits and the questionable need for formal, expensive
hospital-based programs to promote healthy activity. It is apparent, however, that
deconditioning occurs early in the presence of mild disease as symptomatic
subjects increasingly withdraw from activity [65]. It is thus appropriate to advise
patients at all levels of severity to begin a regular training program to reduce
symptoms. Patients who have more advanced disease associated with severe
exertional symptoms, hypoxemia, and possible pulmonary vascular or cardiac
comorbidity should begin therapy in a formal 8- to 12-week supervised program. A
recent meta-analysis reaffirmed the benefits of pulmonary rehabilitation with
respect to improvements in exercise tolerance and symptoms [66]. Other reports
also document that these improvements can be sustained for at least 2 years with an
appropriately supervised maintenance program [67,68]. Furthermore, a reduction
in hospital admissions was found following pulmonary rehabilitation in the context
of a prospective randomized trial [69].

Treatment of exacerbations
COPD exacerbations are important events that can lead to increased costs of
medical care and further disability. While bacterial counts, on average, rise during
exacerbations, this is not a uniform finding. One third of exacerbations have no
identifiable cause or are of viral etiology [70 –72]. It has been confirmed recently
that the presence of exacerbations results in a greater rate of decline in peak flow
and FEV1. By 35 days 25% of subjects and by 91 days more than 7% of subjects
have not fully recovered pulmonary mechanical function following an exacerba-
tion [73]. Furthermore, the impact on quality of life following an exacerbation
appears to be disproportionate to the decrement in simple lung function parameters
[74 –76].
The treatment approach to exacerbations depends on the severity of underlying
disease. More severe patients require more vigilant monitoring because of
decreased respiratory reserve and the greater likelihood of more resistant orga-
 F.C. Sciurba / Chest Surg Clin N Am 13 (2003) 615–629 625

nisms. In all situations treatment should entail more vigorous use of broncho-
dilators, realizing that pulmonary response to short-acting bronchodilators begins
to decline 2 hours after administration. Nebulizer treatment for more severe exac-
erbations, while unproven, is still the standard of care to ensure delivery.
Systemic steroids are indicated for moderate to severe exacerbations and have
been proven to accelerate the rate of improvement in pulmonary function [77];
however, tapering off oral steroids is important to minimize long-term systemic
consequences. An 8-week taper is no more effective than a 2-week taper in
reducing the treatment failure rate [78].
Antibiotic therapy is effective, on average, and should be offered if a patient has
two of the three following symptoms: (1) dyspnea, (2) change in volume of sputum,
or (3) change in color of sputum [79,80]. Patients experiencing repeated exacer-
bations or patients who have FEV1 values less than 50% of predicted are more
likely to harbor resistant organisms and experience treatment failure. Such patients
should be given antibiotics with the broader-spectrum coverage of b lactamase-
producing Haemophius influenza and resistant gram-negative organisms [81,82].
In severe cases associated with pending respiratory failure, noninvasive positive
pressure ventilation has been shown to be an effective strategy in preventing the
costs and medical consequences of intubation and invasive ventilation, although it
is probably less effective when the pH persists below a value of 7.30 [83,84].

Summary
Recent advances in the treatment of patients who have COPD include the
development of long-acting bronchodilators, recognition of the benefits of ICS,
and development of effective initiation and maintenance pulmonary rehabilitation
programs. The focus on outcome parameters other than expiratory flow rates, such
as symptoms, quality of life, exercise tolerance, and exacerbation frequency, might
also allow effective development of novel disease-modifying agents.

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