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1 Department of Internal Medicine, Pulmonary and Critical Care Medicine Section, Nebraska Medical Center, Omaha, Nebraska; and 2 AstraZeneca R&D, Leicestershire, United Kingdom
Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., Professor of Medicine, Department of Internal Medicine, Pulmonary and Critical Care Medicine Section, 985885 University of Nebraska Medical Center, Omaha, NE 68198-5885. E-mail: srennard{at}unmc.edu
ABSTRACT
The seventh Lund COPD workshop focused on exacerbations. As chronic obstructive pulmonary disease (COPD) progresses, exacerbations, events characterized by acute worsening of symptoms, increase in frequency and severity. Patients fear their occurrence, as they compromise function and quality of life, may require admission to the hospital, and can be fatal. There are therapies that improve outcome of exacerbations, such as antibiotics and corticosteroids. More importantly, some treatments, such as regular inhaled bronchodilator therapy (particularly with long-acting agents), inhaled corticosteroids, and vaccination against influenza virus, can partially prevent attacks. However, exacerbations remain a challenge, as no therapy effectively banishes them. The current symposium, "Exacerbation-free COPD, a goal too far?", was designed to address this problem. The challenge addressed by the participants was whether more effective treatments could be developed that could further eliminate COPD exacerbations.
OVERVIEW OF THE MEETING
Chronic obstructive pulmonary disease (COPD) causes loss of lung function that in turn leads to chronic disability with reduced exercise capacity. Both the alveolar wall destruction characteristic of emphysema and the airways disease consequent to bronchitis can contribute to reduced airflow. In addition, there is another clinical characteristic of COPD that it shares with asthma, namely acute exacerbations. The current consensus definition of exacerbation is "a sustained worsening of the patient's condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD."
Acute exacerbations of COPD present a major medical unmet need. Patients fear their occurrence; they are associated with need for medical attention, as usual therapies fail to relieve the increased symptoms. Because of exacerbations, patients may need admission to hospitals for intensive support. Indeed, some 7.4% of patients admitted to hospital may die from the disease (1). These exacerbations that lead to hospitalization are a major source of health care costs associated with COPD.
Presently it has proved possible to reduce the frequency of exacerbations with regular prophylaxis treatment with inhaled long-acting bronchodilators or inhaled glucocorticoids (2), and increased benefits have been observed with combination therapy (3–5). Prevention therapy with influenza and pneumococcal vaccines also has an effect in reducing the frequency of acute exacerbations (6).
Treatment of acute exacerbations with bronchodilators and oxygen is routine, although not tested in randomized trials, which would be regarded as ethically unacceptable. Glucocorticoid therapy of 1 to 2 weeks can improve outcomes (7). Similarly, antibiotics given as acute treatment of COPD exacerbations provide a modest reduction in the severity and duration of exacerbations (8). This is especially seen if the exacerbation is associated with evidence of bacterial infection. Fernando Martinez describes this in detail and the best methods currently available to determine quickly whether bacteria are involved.
However, despite these advances in care, most patients demand more effective therapies. The challenge to medical science and the pharmaceutical industry is to effect a step change in therapy for acute exacerbations of COPD. Advances in scientific 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 highlight two new directions for therapy: (1) prevention of rhinovirus, influenza, and respiratory syncytial virus using specific antivirals; and (2) inhibition of the Toll-like receptors (TLRs) or their signaling pathways. In this regard, the inflammatory response of patients with COPD to viral infections may not be in terms of mediating pathogen clearance. Indeed, the inflammatory response may contribute to the pathogenesis of disease, as pathogens may use the inflammatory responses to enhance their proliferation and infection of new hosts. Thus inhibition of inflammation may improve not only the symptoms that are direct consequences of inflammation, but may also have a beneficial effect on the infection itself.
One of the remaining great uncertainties relating to the morbidity associated with acute exacerbations has been whether they cause an increased rate of decline of lung function. This potential is of considerable importance, as it would effectively link intense bursts of inflammation to the characteristic physiology of COPD, namely loss of FEV1. One of the intriguing observations in the presentation from Ed Silverman is the notion that a genetic susceptibility to infections interacts with the environmental factors causing COPD. A corollary concept is that airways disease and emphysema may have distinct underlying genetic risks. This concept has been suggested in studies of twins (9).
The definition of an acute exacerbation of COPD has been much discussed over the last 80 years. The current consensus view, described above, has been taken further by Paul Jones in his quest to develop a measurement tool that can assess the severity and duration of any exacerbation. He describes the thinking that has been undertaken in the EXACT PRO initiative, an FDA-led academic development of a patient reported outcome (PRO) measurement tool for exacerbations. A consortium of pharmaceutical companies has uniquely sponsored this research. The importance of a clinical definition of exacerbations based on critical symptoms that allow quantification of the severity of these events, rather than a definition based on health care utilization, has been emphasized (10).
A feature of COPD exacerbations is their seasonality, usually occurring in the autumn and winter in the northern and southern hemispheres. Neil Johnston has over the last 3 years taken these observations further, linking the autumn exacerbations with rhinovirus in children returning to school (11), but is still seeking the virus that has been associated with a later peak that he terms the "Christmas epidemic." There is need to confirm the seasonality of exacerbations. However, the prospect is emerging that specific prevention therapy or prophylaxis could be given before the autumn and winter to prevent exacerbation.
The debate as to the pathogen responsible for the exacerbations continues. We see a move away from environmental causes, perhaps reflecting the reduction of airborne pollution in the developed world. Wisia Wedzicha developed the theme that viruses were especially important and probably led to later bacterial infections (12).
Robert Stockley built the argument that in chronic infections of the lungs and acute bacterial infections with organisms, such as Pseudomonas aeruginosa, striking elevations in neutrophil elastase and matrix metalloproteases occur along with myeloperoxidase (13). Such an excessive and persistent inflammatory response could drive the expression of the pathophysiology of the exacerbation.
Tracey Hussell introduced the idea that during the primary response to the pathogen, the frequency of antigen-specific cells are low in the airway and so pathogens are able to replicate unchecked for a significant period of time. This causes bystander tissue damage and the release of high levels of inflammatory cytokines and chemokines. The wave of cells recruited as a consequence, coupled with the high antigen load, causes further, and potentially more extensive, bystander damage. Classically, during a secondary response, antibody and memory T cells are poised to reduce the antigen load. Reduced inflammatory signals and a smaller antigen load results in a more contained and short-lived immune response. The concept was introduced that an infection, acting through the innate immune system, can modify airway responses to subsequent infections. This "memory" can determine the phenotype of the response—that is, it can cause someone to become a "frequent exacerbator"—and offers the potential for therapeutic intervention. In this regard, TLRs are particularly appealing targets (14).
Knowledge about the organization of the pattern recognition TLRs has expanded rapidly over the last 4 years with the identification of the distinct receptors and their ligands. The signaling pathways are being defined and their principle chemokine and cytokine responses described. Herman Wagner, however, 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 potentially therapeutic molecular target (15).
The idea of involvement of the TLRs in a complex interaction between cells, such as monocytes and epithelium, was developed by Ian Sabroe. He proposed a network-based system termed contiguous immunity against which therapies could be directed to reduce the inflammatory responses (16).
Central to devising new therapies to impact on exacerbations is the necessity for accurate diagnosis in individual patients. To this end the separation of airways disease (e.g., bronchitis from pneumonia) is essential, and Eric Hoffmann introduced new imaging methods that could quantify airway wall changes associated with infection. In addition, he described how these methods could separate the disturbance of ventilation consequent to airway disease from altered gas diffusion within the alveoli as might occur in pneumonia (17).
To understand better the dynamics of infection and the subsequent pathophysiological response seen in the COPD exacerbation, Sebastian Johnston described his model system of experimental viral infection in man. Human rhinovirus 16 was administered to the nose of volunteers (18). The time course of the infection, as shown by viral multiplication, was followed, as were upper and lower respiratory symptoms and increases in airflow obstruction. The virus is beginning to be cleared before the peak level of symptoms is seen. Maximal symptoms coincide with a fall in peak expiratory flow rate and a rise in chemokine levels in the nasal secretions. The coincidence of symptoms with the inflammatory responses and airflow obstruction may explain the successful use of corticosteroids in exacerbations (7), which greatly speeds up the recovery of FEV1, for example.
These observations, together with limitations of the rapid methods to diagnose virus infections that were described by Dr. Martinez, mean that treatment of an infection with an antiviral agent would likely be too late to influence the progress of an exacerbation. Alternatively, Dr. Martinez proposed prophylaxis or prevention therapies administered before the patient enters a period of the year that has a high risk of certain infections. He reviewed methods to determine the presence of bacterial infections, ranging from assessment of sputum color to quantification of blood procalcitonin levels (19). Several strategies potential could contribute to "exacerbation-free" COPD. These include treatment with specific antiviral agents or with agents that alter the innate immune system to prevent infections. These could be used either as a prophylaxis during high-risk seasons or prevention therapy before the start of the season.
Anti-inflammatory therapies may also play a role in prevention. In addition to the accelerated resolution of an exacerbation after glucocorticoid treatment, the time to the next exacerbation is extended (7). This links the persistent systemic inflammation as described by Wisia Wedzicha that predicts the recurrence of an exacerbation to a therapeutic intervention that may reduce exacerbation risk.
While current therapy does not result in exacerbation free COPD, the multiplicity of interacting strategies that may prevent exacerbations suggests that the near future could be marked by important gains toward this goal.
FOOTNOTES
Conflict of Interest Statement: S.I.R. has participated as a speaker at programs organized by AstraZeneca (AZ), Boehringer-Ingelheim, GlaxoSmithKline (GSK), Otsuka, and Pfizer. He serves on Advisory Boards for Altana, AZ, Dey, GSK, Novartis, Schering-Plough, and Talecris. He has conducted clinical trials for Almirall, Altana, Astellas, Centocor, GSK, Nabi, Novartis, and Pfizer. He has served as a consultant for Adams, Almirall, Altana, AZ, Bend, Biolipox, Centocor, Critical Therapeutics, GSK, ICOS, Johnson & Johnson, Novartis, Ono, Parengenix, Pfizer, 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 of Nebraska Medical Center. T.H. is a full-time employee of AstraZeneca R&D, UK.
(Received in original form July 12, 2007; accepted in final form July 14, 2007)
REFERENCES
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