Exacerbation-Free COPD: A Goal Too Far?
Stephen I. Rennard1 and Tim Higenbottam2
Department of Internal Medicine, Pulmonary and Critical Care Medicine Section, Nebraska Medical Center, Omaha, Nebraska; and
AstraZeneca R&D, Leicestershire, United Kingdom
The seventh Lund COPD workshop focused on exacerbations. As Treatment of acute exacerbations with bronchodilators and
chronic obstructive pulmonary disease (COPD) progresses, exacer- oxygen is routine, although not tested in randomized trials,
bations, events characterized by acute worsening of symptoms, which would be regarded as ethically unacceptable. Glucocor-
increase in frequency and severity. Patients fear their occurrence, ticoid therapy of 1 to 2 weeks can improve outcomes (7). Sim-
as they compromise function and quality of life, may require ad- ilarly, antibiotics given as acute treatment of COPD exacer-
mission to the hospital, and can be fatal. There are therapies that
bations provide a modest reduction in the severity and duration
improve outcome of exacerbations, such as antibiotics and cortico-
of exacerbations (8). This is especially seen if the exacerbation
steroids. More importantly, some treatments, such as regular in-
haled bronchodilator therapy (particularly with long-acting agents), is associated with evidence of bacterial infection. Fernando
inhaled corticosteroids, and vaccination against inﬂuenza virus, can Martinez describes this in detail and the best methods currently
partially prevent attacks. However, exacerbations remain a chal- available to determine quickly whether bacteria are involved.
lenge, as no therapy effectively banishes them. The current sympo- However, despite these advances in care, most patients de-
sium, ‘‘Exacerbation-free COPD, a goal too far?’’, was designed to mand more effective therapies. The challenge to medical science
address this problem. The challenge addressed by the participants and the pharmaceutical industry is to effect a step change in
was whether more effective treatments could be developed that therapy for acute exacerbations of COPD. Advances in scien-
could further eliminate COPD exacerbations. tiﬁc knowledge about the triggering infections of exacerbations
and the nature of the host primary responses make this goal
reasonable. Several presentations made during the symposium
OVERVIEW OF THE MEETING highlight two new directions for therapy: (1) prevention of rhi-
novirus, inﬂuenza, and respiratory syncytial virus using speciﬁc
Chronic obstructive pulmonary disease (COPD) causes loss of antivirals; and (2) inhibition of the Toll-like receptors (TLRs)
lung function that in turn leads to chronic disability with re- or their signaling pathways. In this regard, the inﬂammatory
duced exercise capacity. Both the alveolar wall destruction char- response of patients with COPD to viral infections may not be
acteristic of emphysema and the airways disease consequent to in terms of mediating pathogen clearance. Indeed, the inﬂam-
bronchitis can contribute to reduced airﬂow. In addition, there matory response may contribute to the pathogenesis of disease,
is another clinical characteristic of COPD that it shares with as pathogens may use the inﬂammatory responses to enhance
asthma, namely acute exacerbations. The current consensus def- their proliferation and infection of new hosts. Thus inhibition of
inition of exacerbation is ‘‘a sustained worsening of the patient’s inﬂammation may improve not only the symptoms that are
condition, from the stable state and beyond normal day-to-day
direct consequences of inﬂammation, but may also have a ben-
variations, that is acute in onset and necessitates a change in
eﬁcial effect on the infection itself.
regular medication in a patient with underlying COPD.’’
One of the remaining great uncertainties relating to the mor-
Acute exacerbations of COPD present a major medical
bidity associated with acute exacerbations has been whether
unmet need. Patients fear their occurrence; they are associated
they cause an increased rate of decline of lung function. This
with need for medical attention, as usual therapies fail to relieve
potential is of considerable importance, as it would effectively
the increased symptoms. Because of exacerbations, patients
may need admission to hospitals for intensive support. Indeed, link intense bursts of inﬂammation to the characteristic physi-
some 7.4% of patients admitted to hospital may die from the ology of COPD, namely loss of FEV1. One of the intriguing
disease (1). These exacerbations that lead to hospitalization are observations in the presentation from Ed Silverman is the
a major source of health care costs associated with COPD. notion that a genetic susceptibility to infections interacts with
Presently it has proved possible to reduce the frequency of the environmental factors causing COPD. A corollary concept
exacerbations with regular prophylaxis treatment with inhaled is that airways disease and emphysema may have distinct under-
long-acting bronchodilators or inhaled glucocorticoids (2), and lying genetic risks. This concept has been suggested in studies of
increased beneﬁts have been observed with combination ther- twins (9).
apy (3–5). Prevention therapy with inﬂuenza and pneumococcal The deﬁnition of an acute exacerbation of COPD has been
vaccines also has an effect in reducing the frequency of acute much discussed over the last 80 years. The current consensus
exacerbations (6). view, described above, has been taken further by Paul Jones in
his quest to develop a measurement tool that can assess the
(Received in original form July 12, 2007; accepted in ﬁnal form July 14, 2007) severity and duration of any exacerbation. He describes the
Correspondence and requests for reprints should be addressed to Stephen thinking that has been undertaken in the EXACT PRO initia-
I. Rennard, M.D., Professor of Medicine, Department of Internal Medicine, tive, an FDA-led academic development of a patient reported
Pulmonary and Critical Care Medicine Section, 985885 University of Nebraska outcome (PRO) measurement tool for exacerbations. A con-
Medical Center, Omaha, NE 68198-5885. E-mail: email@example.com
sortium of pharmaceutical companies has uniquely sponsored
Proc Am Thorac Soc Vol 4. pp 583–585, 2007
DOI: 10.1513/pats.200707-098TH this research. The importance of a clinical deﬁnition of exacer-
Internet address: www.atsjournals.org bations based on critical symptoms that allow quantiﬁcation of
584 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 4 2007
the severity of these events, rather than a deﬁnition based on To understand better the dynamics of infection and the
health care utilization, has been emphasized (10). subsequent pathophysiological response seen in the COPD
A feature of COPD exacerbations is their seasonality, exacerbation, Sebastian Johnston described his model system
usually occurring in the autumn and winter in the northern and of experimental viral infection in man. Human rhinovirus 16
southern hemispheres. Neil Johnston has over the last 3 years was administered to the nose of volunteers (18). The time course
taken these observations further, linking the autumn exac- of the infection, as shown by viral multiplication, was followed,
erbations with rhinovirus in children returning to school (11), as were upper and lower respiratory symptoms and increases in
but is still seeking the virus that has been associated with a later airﬂow obstruction. The virus is beginning to be cleared before
peak that he terms the ‘‘Christmas epidemic.’’ There is need to the peak level of symptoms is seen. Maximal symptoms coincide
conﬁrm the seasonality of exacerbations. However, the prospect with a fall in peak expiratory ﬂow rate and a rise in chemokine
is emerging that speciﬁc prevention therapy or prophylaxis could levels in the nasal secretions. The coincidence of symptoms with
be given before the autumn and winter to prevent exacerbation. the inﬂammatory responses and airﬂow obstruction may explain
The debate as to the pathogen responsible for the exacer- the successful use of corticosteroids in exacerbations (7), which
bations continues. We see a move away from environmental greatly speeds up the recovery of FEV1, for example.
causes, perhaps reﬂecting the reduction of airborne pollution in These observations, together with limitations of the rapid
the developed world. Wisia Wedzicha developed the theme that methods to diagnose virus infections that were described by Dr.
viruses were especially important and probably led to later Martinez, mean that treatment of an infection with an antiviral
bacterial infections (12). agent would likely be too late to inﬂuence the progress of an
Robert Stockley built the argument that in chronic infections exacerbation. Alternatively, Dr. Martinez proposed prophylaxis
of the lungs and acute bacterial infections with organisms, such or prevention therapies administered before the patient enters
as Pseudomonas aeruginosa, striking elevations in neutrophil a period of the year that has a high risk of certain infections.
elastase and matrix metalloproteases occur along with myelo- He reviewed methods to determine the presence of bacterial
peroxidase (13). Such an excessive and persistent inﬂammatory infections, ranging from assessment of sputum color to quanti-
response could drive the expression of the pathophysiology of ﬁcation of blood procalcitonin levels (19). Several strategies
the exacerbation. potential could contribute to ‘‘exacerbation-free’’ COPD. These
Tracey Hussell introduced the idea that during the primary include treatment with speciﬁc antiviral agents or with agents
response to the pathogen, the frequency of antigen-speciﬁc cells that alter the innate immune system to prevent infections.
are low in the airway and so pathogens are able to replicate These could be used either as a prophylaxis during high-risk
unchecked for a signiﬁcant period of time. This causes bystander seasons or prevention therapy before the start of the season.
tissue damage and the release of high levels of inﬂammatory Anti-inﬂammatory therapies may also play a role in pre-
cytokines and chemokines. The wave of cells recruited as a con- vention. In addition to the accelerated resolution of an exacer-
sequence, coupled with the high antigen load, causes further, and bation after glucocorticoid treatment, the time to the next
potentially more extensive, bystander damage. Classically, dur- exacerbation is extended (7). This links the persistent systemic
ing a secondary response, antibody and memory T cells are poised inﬂammation as described by Wisia Wedzicha that predicts the
to reduce the antigen load. Reduced inﬂammatory signals and recurrence of an exacerbation to a therapeutic intervention that
a smaller antigen load results in a more contained and short-lived may reduce exacerbation risk.
immune response. The concept was introduced that an infection, While current therapy does not result in exacerbation free
acting through the innate immune system, can modify airway COPD, the multiplicity of interacting strategies that may prevent
responses to subsequent infections. This ‘‘memory’’ can deter- exacerbations suggests that the near future could be marked by
mine the phenotype of the response—that is, it can cause important gains toward this goal.
someone to become a ‘‘frequent exacerbator’’—and offers the
Conﬂict of Interest Statement: S.I.R. has participated as a speaker at programs
potential for therapeutic intervention. In this regard, TLRs are organized by AstraZeneca (AZ), Boehringer-Ingelheim, GlaxoSmithKline (GSK),
particularly appealing targets (14). Otsuka, and Pﬁzer. He serves on Advisory Boards for Altana, AZ, Dey, GSK,
Knowledge about the organization of the pattern recognition Novartis, Schering-Plough, and Talecris. He has conducted clinical trials for
Almirall, Altana, Astellas, Centocor, GSK, Nabi, Novartis, and Pﬁzer. He has served
TLRs has expanded rapidly over the last 4 years with the as a consultant for Adams, Almirall, Altana, AZ, Bend, Biolipox, Centocor, Critical
identiﬁcation of the distinct receptors and their ligands. The Therapeutics, GSK, ICOS, Johnson & Johnson, Novartis, Ono, Parengenix, Pﬁzer,
signaling pathways are being deﬁned and their principle chemo- Roche, Sankyo, Sanoﬁ, and Shering-Plough. A patent is pending on a method for
stem cell differentiation; he is a co-inventor of the patent owned by the University
kine and cytokine responses described. Herman Wagner, how- of Nebraska Medical Center. T.H. is a full-time employee of AstraZeneca R&D, UK.
ever, emphasized the need to consider speciﬁcally molecular
constructs that are involved in the pattern recognition. His work
in this area has considerable importance in selecting any poten-
tially therapeutic molecular target (15). References
The idea of involvement of the TLRs in a complex inter- 1. Price LC, Lowe D, Hosker HS, Anstey K, Pearson MG, Roberts CM.
action between cells, such as monocytes and epithelium, was de- UK National COPD Audit 2003: Impact of hospital resources and
veloped by Ian Sabroe. He proposed a network-based system organisation of care on patient outcome following admission for acute
termed contiguous immunity against which therapies could be COPD exacerbation. Thorax 2006;61:837–842.
2. Sin DD, McAlister FA, Man SF, Anthonisen NR. Contemporary
directed to reduce the inﬂammatory responses (16). management of chronic obstructive pulmonary disease: scientiﬁc
Central to devising new therapies to impact on exacerbations review. JAMA 2003;290:2301–2312.
is the necessity for accurate diagnosis in individual patients. To 3. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H.
this end the separation of airways disease (e.g., bronchitis from Maintenance therapy with budesonide and formoterol in chronic
pneumonia) is essential, and Eric Hoffmann introduced new obstructive pulmonary disease. Eur Respir J 2003;22:912–919.
imaging methods that could quantify airway wall changes associ- 4. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW,
Yates JC, Vestbo J. Salmeterol and ﬂuticasone propionate and survival in
ated with infection. In addition, he described how these methods
chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.
could separate the disturbance of ventilation consequent to air- 5. Niewoehner DE, Rice K, Cote C, Paulson D, Cooper JA Jr, Korducki L,
way disease from altered gas diffusion within the alveoli as might Cassino C, Kesten S. Prevention of exacerbations of chronic ob-
occur in pneumonia (17). structive pulmonary disease with tiotropium, a once-daily inhaled
Rennard and Higenbottam: A Goal Too Far? 585
anticholinergic bronchodilator: a randomized trial. Ann Intern Med 13. Papi A, Luppi F, Franco F, Fabbri LM. Pathophysiology of exacerba-
2005;143:317–326. tions of chronic obstructive pulmonary disease. Proc Am Thorac Soc
6. Poole PJ, Chacko E, Wood-Baker RW, Cates CJ. Inﬂuenza vaccine 2006;3:245–251.
for patients with chronic obstructive pulmonary disease. Cochrane 14. Walzl G, Tafuro S, Moss P, Openshaw PJ, Hussell T. Inﬂuenza virus lung
Database Syst Rev 2006;1:CD002733. infection protects from respiratory syncytial virus-induced immuno-
7. Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light pathology. J Exp Med 2000;192:1317–1326.
RW, Anderson P, Morgan NA. Effect of systemic glucocorticoids on 15. Spiller S, Dreher S, Meng G, Grabiec A, Thomas W, Hartung T,
exacerbations of chronic obstructive pulmonary disease. N Engl J Pfeffer K, Hochrein H, Brade H, Bessler W, et al. Cellular
Med 1999;340:1941–1947. recognition of trimyristoylated peptide or enterobacterial lipopoly-
8. Ram FS, Rodriguez-Roisin R, Granados-Navarrete A, Garcia-Aymerich saccharide via both TLR2 and TLR4. J Biol Chem 2007;282:13190–
J, Barnes NC. Antibiotics for exacerbations of chronic obstructive 13198.
pulmonary disease. Cochrane Database Syst Rev 2006;2:CD004403. 16. Sabroe I, Dockrell DH, Vogel SN, Renshaw SA, Whyte MK, Dower SK.
9. Hallberg J, Dominicus A, Eriksson UK, Gerhardsson de Verdier G, Identifying and hurdling obstacles to translational research. Nat Rev
Pedersen NL, Dahlback M, Nihlen U, Higenbottam T, Svarengren M. Immunol 2007;7:77–82.
Interaction between smoking and genetic factors in the development 17. Chon D, Beck KC, Simon BA, Shikata H, Saba OI, Hoffman EA. Effect
of chronic bronchitis. Am J Respir Crit Care Med (In press) of low-xenon and krypton supplementation on signal/noise of regional
10. Calverley P, Pauwels Dagger R, Lofdahl CG, Svensson K, Higenbottam CT-based ventilation measurements. J Appl Physiol 2007;102:1535–
T, Carlsson LG, Stahl E. Relationship between respiratory symptoms 1544.
and medical treatment in exacerbations of COPD. Eur Respir J 18. Papi A, Contoli M, Gaetano C, Mallia P, Johnston SL. Models of in-
2005;26:406–413. fection and exacerbations in COPD. Curr Opin Pharmacol 2007;7:
11. Johnston NW, Sears MR. Asthma exacerbations. 1: epidemiology. Thorax 259–265.
2006;61:722–728. 19. Stolz D, Christ-Crain M, Bingisser R, Leuppi J, Miedinger D, Muller C,
12. Hurst JR, Donaldson GC, Wilkinson TM, Perera WR, Wedzicha JA. Huber P, Muller B, Tamm M. Antibiotic treatment of exacerbations
Epidemiological relationships between the common cold and exacer- of COPD: a randomized, controlled trial comparing procalcitonin-
bation frequency in COPD. Eur Respir J 2005;26:846–852. guidance with standard therapy. Chest 2007;131:9–19.