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Only 40% of all respondents-45.1% professional staff and 26.1% technical/support staff -felt it was likely they would be asked by their health department to respond to a pandemic influenza related emergency. Perception of Table 2) . Perception of one's existing knowledge about pandemic influenza, and perception of having an important role in the agency's overall response were significantly higher among professional staff compared to technical/support staff (Figure 1 ), In multivariate analysis, increased self-described likelihood of reporting to work during an influenza pandemic emergency was significantly associated with agreement with several constructs, most notably perception of the capacity to communicate risk effectively, perception of the importance of one's role in the agency's overall response, and familiarity with one's role-specific response requirements in a pandemic influenza related emergency. ( Table 2 ).
The vast majority (83%) of the respondents felt they would benefit from additional training activities. A lower perceived level of familiarity with one's role was not significantly associated with a higher perceived need for additional training ( (Figure 2 ).
The World Health Organization has urged all countries to prepare for the next influenza pandemic, which it termed . The federally adopted U.S. model of all-hazards emergency readiness has presented local health departments with new organizational challenges and learning curves. The all-hazards approach entails an ability and willingness to respond to a broad spectrum of disasters, ranging from the intentional (e.g., chemical, biological, or radiological terror) to the naturally occurring (e.g., weather-related crises or non-bioterrorism related infectious disease) [14] .
Current national contingency plans account for possible personnel shortages within the healthcare and public health settings, mainly due to the expected influenza morbidity among workers. Yet our data suggest that regardless of the expected morbidity among personnel during an influenza pandemic, nearly half of the local health department workers are likely not to report to duty during such an extreme public health crisis. In fact, most of the workers (and nearly three out of four technical/support workers) do not believe they will even be asked to report to work.
We have found that the willingness to report to duty during a pandemic varies considerably according to the individual's job classification. Clinical staff state they are significantly more likely to report to duty, compared with all other workers. This difference correlates well with the single most influential construct associated with willingness to report to duty -the perception of the importance of one's role in the agency's overall response. Less than a third of the respondents believed they will have an important role in the agency's response to local outbreaks of pandemic influenza, but within this subgroup, willingness to report to duty was as high as 86.8%. Belief in the importance of one's role was lowest among technical/support staff, environmental health staff, and other non-clinical professional staff (15.1%, 18.4% and 18.8% respectively), groups in which willingness to report was shown to be lowest. We therefore believe further efforts must be directed at ensuring that all local public health workers, but most notably non-clinical professional staff, understand in advance the importance of their role during an influenza pandemic -otherwise they will fail to show up when they are most needed.
Our findings fit well in the theoretical framework emphasizing risk communication needs of public health workers, who themselves serve as risk communicators [9] . Several factors, previously suggested to be risk perception "modifiers" [9] of substantial impact on public health
Proportion of individuals who agreed with each of the attitude and belief constructs by staff type Figure 1 Proportion of individuals who agreed with each of the attitude and belief constructs by staff type.
Technical/Support Staff Professional Staff * * workforce's response to a crisis, indeed proved to be important in this context. Lack of knowledge, ambiguity regarding one's exact tasks, and questionable ability in performing one's role as risk communicator were all significantly associated with a higher perceived personal risk and a two-to ten-fold decrease in willingness to report to duty; these factors proved to be more influential even than the perceived level of family preparedness to function in one's absence. It is therefore important to recognize that public health employees, who are intended to serve as purveyors of risk communication for their communities, themselves represent a community with specific perceptions that must be addressed in the context of emergency readiness training.
The threat of an impending influenza pandemic is not a new one -pandemics have been taking place once every several decades for over 300 years. Yet it was only in the last couple of years, as highly pathogenic H5N1 strain became increasingly endemic in southeast Asia and as lethal infections with the virus occurred in an alarmingly increasing rate among humans, that the urgency of the situation was openly declared by national and international health authorities. The rapidity of this evolving situation may serve to explain why only one third of the respondents felt they were adequately knowledgeable on pan-demic influenza, and why only one in five respondents felt capable in effectively communicating pandemic risks. This finding is especially noteworthy, in that members of the public health support staff may become frontline telephone risk communicators in a crisis, serving as the first points of interface for concerned callers contacting a health department. Only one of the 35 technical/support staff workers who felt incapable of effective risk communication was willing to report to duty, even though most of them believed the health department will have the ability to provide timely information.
The study has some relevant limitations that must be factored into the overall analysis. First, the sample was limited to three non-randomly selected health departments, none of which serves a community larger than 250,000 residents, and all of which have staff sizes under 250. The sample size of 308 survey employees limited this study's power. As the study includes Maryland health departments only, it does not account for potential jurisdictional or regional variations nationwide in response capacity or risk perceptions toward pandemic influenza response. Furthermore, the job classifications -based on those used to develop the CDC-adopted emergency preparedness competencies [15] -do not necessarily map neatly onto functional responsibilities in disaster Odds Ratios of reporting to work in case of a pandemic-influenza-related emergency by staff and attitude or belief construct Figure 2 Odds Ratios of reporting to work in case of a pandemic-influenza-related emergency by staff and attitude or belief construct.
Technical/Support Staff Professional Staff response. For example, health educators may play as frontline a role as clinical staff, in terms of their degree of interface with the public in a disaster. Our job categories therefore do not necessarily reflect the relative impacts of job-specific cohorts on disaster response in the event that they do not report to work.
We assessed the presence and the direction of nonresponse bias by comparing the distribution of personal characteristics for the respondents and for all health department personnel. The lack of significant difference in age and gender distribution, as well as the lack of significant difference in job classification other than technical/ support staff indicates that the extent of such a bias in the study is probably limited. The small yet statistically significant over-representation of technical/support staff in our study group may potentially have caused a slight underestimation of overall willingness to report. However, as the internal associations between the various variables were also studied separately for the technical/support staff and professional staff (Figure 2) , this over-representation should not impact the general conclusions presented above.
Having accounted for these limitations, it is important to note that the findings were internally consistent among the three surveyed health departments. Although none of the health departments served large metropolitan areas and all had fewer than 250 employees, it must also be recognized that only 4% of the nation's local health departments serve populations of 500,000 or more, and that local public health agencies tend to have small staff sizes (with a median of 13 full time employees) [12] .
Interestingly, our findings show similar patterns to data on the willingness of urban healthcare workers from nonpublic health settings to respond to emergencies: a survey of 6248 employees from 47 healthcare facilities in the New York City area revealed that these workers were least willing (48%) to report to duty during an untreatable naturally-occurring infectious disease outbreak affecting their facility (SARS), compared to other disaster scenarios [5] . In our study we have detected similar rates of likelihood to report to duty, although lower rates could have been expected in our study population since the New York City survey focused on healthcare workers whose organizational cultures are historically much more accustomed than that of local public health workers to emergency response, in a city with a heightened awareness of disaster preparedness in the wake of the World Trade Center attacks and subsequent anthrax attacks [5] .
In the face of a pandemic influenza threat, local health department employees' unwillingness to report to duty may pose a threat to the nation's emergency response infrastructure. Addressing the specific factors associated with this unwillingness is necessary to help ensure that existing local health department preparedness competencies [15] will translate into the scope of response described in the nation's pandemic influenza plans [2] . Interventions suggested to enhance the willingness of healthcare workers in non-public health department settings to report to duty in disasters include workforce preparedness education [5] , provision of appropriate personal protective equipment, [4, 14] crisis counseling, family preparedness and social support [5, 16] .
These recommendations fit well within the framework of our findings, and we further recommend that such education programs include specialized training emphasizing the specific nature of, and guidelines for, one's role in response to pandemic influenza; the relevance of each worker's role in the effectiveness of an overall public health response; and the workers' ability to provide effective risk communication. Additional research must further focus on best practice models for addressing the above described gaps in local public health response to this urgent public health threat.
These data offer a current, evidence-based window into the needs of public health workers who would serve as a backbone of locally-driven emergency response in an influenza pandemic setting. We found that most of these workers feel they will work under significant personal risk, in a scenario they are not adequately knowledgeable about, performing a role they are not sufficiently trained for, and believing this role does not have a significant impact on the agency's overall response. These specific perceptions and needs must be attended, and specific intervention programs must be initiated. In order to reduce the perceived risk associated with the worker's role in an influenza pandemic, each worker must have better understanding of the scenario and importance of his or her personal role within these settings, confidence that the agency will provide adequate protective equipment for its employees, psychological support and timely information, and a belief of being well-trained to cope with emergency responsibilities including the ability to communicate risk to others. In view of what is currently considered to be an impending influenza pandemic, a wide gap between these desired targets and current status exists, that may lead to significant hindrance in the ability of local health departments to function adequately. On pandemics and the duty to care: whose duty? who cares? BACKGROUND: As a number of commentators have noted, SARS exposed the vulnerabilities of our health care systems and governance structures. Health care professionals (HCPs) and hospital systems that bore the brunt of the SARS outbreak continue to struggle with the aftermath of the crisis. Indeed, HCPs – both in clinical care and in public health – were severely tested by SARS. Unprecedented demands were placed on their skills and expertise, and their personal commitment to their profession was severely tried. Many were exposed to serious risk of morbidity and mortality, as evidenced by the World Health Organization figures showing that approximately 30% of reported cases were among HCPs, some of whom died from the infection. Despite this challenge, professional codes of ethics are silent on the issue of duty to care during communicable disease outbreaks, thus providing no guidance on what is expected of HCPs or how they ought to approach their duty to care in the face of risk. DISCUSSION: In the aftermath of SARS and with the spectre of a pandemic avian influenza, it is imperative that we (re)consider the obligations of HCPs for patients with severe infectious diseases, particularly diseases that pose risks to those providing care. It is of pressing importance that organizations representing HCPs give clear indication of what standard of care is expected of their members in the event of a pandemic. In this paper, we address the issue of special obligations of HCPs during an infectious disease outbreak. We argue that there is a pressing need to clarify the rights and responsibilities of HCPs in the current context of pandemic flu preparedness, and that these rights and responsibilities ought to be codified in professional codes of ethics. Finally, we present a brief historical accounting of the treatment of the duty to care in professional health care codes of ethics. SUMMARY: An honest and critical examination of the role of HCPs during communicable disease outbreaks is needed in order to provide guidelines regarding professional rights and responsibilities, as well as ethical duties and obligations. With this paper, we hope to open the social dialogue and advance the public debate on this increasingly urgent issue. In 2003, the world witnessed the spread of a novel and deadly virus, namely SARS CoV. The health care workers (HCWs) and hospital systems that bore the brunt of the SARS outbreak continue to struggle with the aftermath of the crisis. Indeed, HCWs -both in clinical care and in public health -were severely tested by SARS. Unprecedented demands were placed on their skills and expertise, and their personal commitment to their profession was severely tried. Many were exposed to serious risk of morbidity and mortality; indeed, approximately 30% of reported cases were among HCWs, some of whom died from the infection [1] .
As a number of commentators have noted, SARS exposed the vulnerabilities of our current health care systems and governance structures [2] [3] [4] . The aftermath of SARS and the spectre of pandemic avian influenza make imperative the need to consider the obligations of HCWs for patients with severe infectious diseases, particularly diseases that pose risks to those providing care. It is of pressing importance that organizations representing HCWs -professionals and non-professionals alike -give clear indication of what standard of care is expected of their members in the event of a pandemic.
Many experts believe that the SARS outbreak was merely a preview of the next flu pandemic that is soon to arrive, possibly from an avian influenza virus [5] . Quite clearly, avian flu threatens to be more widespread than SARS, with the potential to become a truly global pandemic. An honest and critical examination of the role of HCWs during such a crisis is needed in order to provide guidelines regarding professional rights and responsibilities, as well as ethical duties and obligations [6] .
In this paper, we address the issue of special obligations of health care professionals (HCPs) during an infectious disease outbreak. We contend that there is a pressing need to clarify the rights and responsibilities of HCPs, especially in the current context of pandemic flu preparedness. Moreover, we argue that these rights and responsibilities would best be codified in professional codes of ethics. Finally, we present a brief historical account of the treatment of the duty to care in professional health care codes of ethics with the intention of opening the social dialogue and advancing the public debate on this increasingly relevant issue.
Given that the response by HCPs to the SARS crisis was generally regarded as exemplary, one might ask whether an ethical problem truly exists. There is little doubt that the vast majority of HCPs performed their jobs admirably under considerable stress and significant personal risk. Many HCPs provided exemplary care, and still others behaved in truly heroic fashion. So why, then, formally problematize something that is not a problem?
As noted, many HCPs acted in a supererogatory manner during the SARS outbreak [7], none more so than Dr. Carlo Urbani of the World Health Organization, who himself died of SARS after being exposed to the yet unknown virus in the course of carrying out his professional duties. Likewise, scores of nurses, doctors, respiratory technicians, and other professional and nonprofessional health workers laboured extremely long hours at personal risk. This demonstration of going above and beyond the call of duty, which proved necessary to control the disease, was highly morally commendable.
At the same time, however, serious concerns did surface during SARS about the extent to which HCPs would tolerate risks of infection [8, 9] . Some baulked at providing care to those infected with the unknown virus. In some circumstances, staffing became an issue in SARS wards and assessment centres; indeed, failure to report for duty during the outbreak resulted in the permanent dismissal of some hospital staff. As a consequence, the risk that was faced during SARS was not distributed equitably, and those HCPs who volunteered to provide care faced the greatest exposure.
Following the outbreak, many of those who treated SARS patients raised concerns about the protections that were provided to safeguard their own health and that of their family members. Conflicting obligations were another significant concern. HCPs are bound by an ethic of care, therefore, obligations to the patient's well-being should be primary. At the same time, however, HCPs have competing obligations to their families and friends, whom they feared infecting, in addition to obligations to themselves and to their own health (particularly those with special vulnerabilities, such as a co-morbid condition). During SARS, some HCPs questioned their choice of career; indeed, some decided to leave their profession and pursue new ventures, indicating an unwillingness or inability to care for patients in the face of risk. Recent survey data from the U.S. indicate that there exists mixed views on the duty to care for patients during infectious disease outbreaks [10] .
What is clear is this: the issue of duty to care has emerged as a matter of paramount concern among health care professionals, hospital administrators, public policy makers, and bioethicists [11] [12] [13] [14] .
The ethical foundations of the duty to provide care are grounded in several longstanding ethical principles. Foremost among these is the principle of beneficience, which recognizes and defines the special moral obligation on the part of HCPs to further the welfare of patients and to advance patients' well-being. In modern health care, it is commonly understood and generally accepted that the principle of beneficence constitutes a foundational principle of the patient-provider relationship [15] .
For the HCP in general, and for the physician in particular, there are a number of compelling reasons to provide care in the context of an infectious disease outbreak. Clark [12] has recently outlined three such reasons:
1. The ability of physicians and health care professionals to provide care is greater than that of the public, thus increasing the obligation to provide care Although self-care and self-protection, as well as the care and protection of friends and family members, are acknowledged in pandemic plans, it is evident that the expertise of HCPs is an integral and principal component of the response to a pandemic. There is no other sector of society that can be legitimately expected to fulfil this role and to assume this level of risk.
Arguably, HCPs have consented to greater than average risk by their very choice of profession. While it may be granted that the risk of contracting an infectious disease was likely not a concern for a generation of prospective health care workers, any informed reading of the medical literature in the last 20 years has shown that infectious diseases remain ubiquitous and problematic -notwithstanding overly-optimistic statements regarding the future threat of infectious diseases. It is therefore not unreasonable to argue that HCPs were aware of the greater than average risks posed by their choice of profession.
In publicly-funded health care systems, such as those found in many Western societies, there is a strong claim for a social contract between the HCP and society. It is a reasonable and legitimate expectation by the public that HCPs will respond in an infectious disease emergency. Society has granted and permits professions to be self-regulating on the understanding that such a response would occur.
One of the characteristics of a self-regulating profession is the development of standards of practice, sometimes referred to as best practice guidelines. These standards are articulated in professional codes of ethics, which are developed on the basis of the fundamental principles and values of the particular profession, as is the case, for instance, with respect to the codes of ethics that were developed long ago in medicine and nursing. Indeed, the code of ethics has a long and respected tradition in the health professions and today most, if not all, the various health and social care professions have codes of ethics in place to provide guidance to their members.
The code of ethics is sometimes referred to as an instrument of "soft law," owing to its non-legislative nature [16] . As such, in the health care professions, codes of ethics should be interpreted as guides for ethical reasoning and frameworks for the treatment of individual patients, rather than as substitutes for such reasoning or as an absolute mandate [17] . At the same time, a code that is too vague can render it ineffectual and irrelevant. In an era in which health care and technology are evolving at a rapid pace, efforts are necessary to ensure that codes of ethics remain current, practical, and concordant with public expectations.
An informative and comprehensible code of ethics has numerous tangible benefits. Perhaps the greatest benefit would be to dispel confusion and uncertainty for HCPs concerning their professional rights and responsibilities as regards the duty to care. Of course, a detailed treatment of the issue in professional codes of ethics would also serve to increase awareness and comfort levels, perhaps resulting in increased willingness to provide care in uncertain and risky conditions [18] . Additionally, codes guiding professional conduct may effectively serve as norms of standards recognizable and enforceable by law, acting as the foundation of legal obligations and decisions [16] .
Finally, codes of ethics also serve as potent forms of symbolic communication to the public that is served by the professions. By making explicit the values that health care professions represent, professional codes of ethics can reassure the public that the trust invested in the professions is justified and legitimate, as is properly noted in the following excerpt from the College of Nurses of Ontario Practice Standard on Ethics:
"Nurses have a commitment to the nursing profession. Being a member of the profession brings with it the respect and trust of the public. To continue to deserve this respect, nurses have a duty to uphold the standards of the profession.... As members of a self-regulating profession, nurses also have a commitment to help regulate nursing to protect the public's right to quality nursing services. It is in the public's interest that the profession continue to regulate itself by developing and changing the methods of self-regulation to meet the changes in health care and society. Nurses have an obligation to participate in the effective evolution of self-regulation. Self-regulation is a privilege and each nurse is accountable for the responsibilities that accompany this privilege." [19] What do current codes of ethics say regarding duty to care during epidemics? It is of no small concern that many current professional codes of ethics fail to provide explicit guidance sufficient to set policy or assure the public in the event of an infectious disease outbreak. The Canadian Medical Association, for instance, released a revised Code of Ethics in 2004, one year after the SARS pandemic in which Canada was particularly affected [20] . Despite the seemingly fortuitous timing of the publication, the revised Code is, quite astoundingly, altogether silent on physicians' duty to care, which might be described as the first among equals of the myriad ethical dilemmas that emerged during the global outbreak.
The key revision in the 2004 edition of the CMA Code was the addition of the following item to the 'Fundamental Responsibilities' section: "Consider the well-being of society in matters affecting health" [20] . This addition, however, does little to address, in any substantively meaningful way, the duty to care obligations of HCPs in the context of an infectious disease outbreak. Does the addition of this responsibility obligate physicians to provide treatment even when doing so would put their own health in peril? The wording is too vague to be of any significant guidance in clinical practice.
In contrast, the American Medical Association (AMA) appears to have recognized the present need to address the issue of duty to care. In the wake of the 9/11 terrorist attack, the AMA has adopted several new ethics policies that focus specifically on the medical profession's obligations and responsibilities in the context of a public health emergency. The following passage is from the AMA policy document "Physician Obligation in Disaster Preparedness and Response" that was adopted in June 2004: "National, regional, and local responses to epidemics, terrorist attacks, and other disasters require extensive involvement of physicians. Because of their commitment to care for the sick and injured, individual physicians have an obligation to provide urgent medical care during disasters. This ethical obligation holds even in the face of greater than usual risks to their own safety, health or life. The physician workforce, however, is not an unlimited resource; therefore, when participating in disaster responses, physicians should balance immediate benefits to individual patients with ability to care for patients in the future." [21] While the AMA has taken a step in the right direction by stating the obligations of its members, and it is to its great credit for initiating this process, it remains to be seen whether other national medical associations and other health care professions will follow suit and redress the silence of codes of ethics on the duty to provide care.
To some extent, codes of ethics can be seen as reflections of enduring professional values. At the same time, they are also clearly influenced by and are the product of historical circumstances. The CMA, for instance, previously included in its Code of Ethics a strongly worded statement explicitly addressing the obligations of physicians in infectious disease outbreaks. The 1922 version reads as follows: "When pestilence prevails, it is their [physicians'] duty to face the danger, and to continue their labours for the alleviation of suffering, even at the jeopardy of their own lives" [22] . This is the only appearance in the CMA Code of this type of strong categorical language regarding the professional duty to care. Interestingly, the specific text cited above appears for the first time in the revision following the 1919 influenza pandemic and then, conspicuously, disappears from the next revision released in 1926.
The AMA included the very same provision in its Code of Ethics from 1846 through until the 1970s when it was likewise excised. This marked professional retrenchment from a strong obligation to provide care -as reflected in current codes of ethics -is attracting increased interest of late. A number of explanations have been proposed by academic commentators. For instance, the retrenchment has been linked to the rise of government and corporate intrusions into medical practice [23] . Others, including Clark [12] , have pointed to an increasing general belief originating circa 1950 that infectious diseases had been vanquished. It is most likely the case that both these factors played a significant role in the observed retrenchment over time.
Irrespective of the reasons underlying the current silence, there can be little doubt that infectious diseases are an increasing clinical reality in the developed world, and have long been a tremendous challenge in the developing world. For this reason alone, the continuing silence of codes of ethics is greatly problematic, both clinically and normatively.
There is no current consensus as to how explicitly and stringently the requirements for the duty to care should be stated [14] . In a 2003 survey of 1000 American physicians, respondents reported decidely mixed views on whether they would continue to care for patients in the event of an outbreak. Given that only a narrow majority of the surveyed physicians reported believing in a professional duty to treat patients in epidemics, the authors of the study concluded that there should be a reinforcement of "the [medical] profession's ethical duty to treat" in the event of a public health crisis [10] .
This call for the reinforcement of the duty to care echoes the 1922 CMA Code of Ethics that clearly stipulates that physicians have a duty to provide care, even at the jeopardy of their own lives. This statement may indeed be considered too strong and too categorical by many today. To require the provision of care even when doing so entails significant risk to the provider would appear to be demanding that all HCPs behave like "supreme Samaritans" [12] . Is this reasonable? Is this ethical? These remain open questions, but it is doubtful that all HCPs would adhere to such stringent obligations when faced with a SARS-like crisis. As Emmanuel [24] has instructively noted, the historical record of physicians is decidedly mixed in this regard; indeed, it was in response to the vocal and mounting opposition to treating seropositive patients at the height of the HIV/AIDS epidemic in the 1980s that the medical profession reconsidered the ongoing retrenchment of the duty to care. With the threat of a new epidemic, another round of full and open discourse is required as to whether the acceptable standard of professional engagement should occur at the level of "supreme", "good", or "merely decent" Samaritan [12] .
There is presently a need to address the professional duties of HCPs to their patients with the risks to the well-being of society, which may include family, friends, co-workers, and other patients, in addition to the population at large. This is a matter of balance. The content of current professional codes of ethics offers little guidance or reflection of consensus in the health care community. In the wake of SARS and with the current threat of avian influenza, it is clearly time for medicine, nursing, and other self-regulating health care professions to address the issue head on.
A number of options are open to the professions. One option, which we have already argued is unacceptable, would be to remain silent. On the other extreme, codes of ethics could be revised with a strong emphasis on the professional obligation and duty to provide care during infectious disease emergencies; that is, assume a position leaning towards supererogation, or performing acts that are 'above the call' of duty [7] . Several other options exist between these two extremes. For instance, the codes could reflect a strong but limited duty to care, with the limits clearly specified. Alternatively, there could be a weak emphasis on duty to care -an option more sympathetic to the self-regarding concerns of HCPs [8] -although this may run the risk of dissolution of the generally high regard for the health care professions that exists in society today.
We maintain that, with respect to the duty to care, it is not acceptable for codes of ethics to be vague, ambiguous, or otherwise avoid explicit statements of position. This is particularly true in light of calls for additional protections for HCPs during infectious disease outbreaks, including a position statement to that effect issued by the Ontario Medical Association [25] . Such calls for danger pay and/or enhanced disability insurance could be justified if the professions expressed a strong commitment to the ethical duty to provide care during public health emergencies. In the absence of such commitment, however, any additional measures to protect and safeguard the well-being of HCPs would appear self-serving and misplaced.
In the current context of pandemic influenza planning, as with other public health emergencies, there is an acute need for strategies to encourage greater discussion and dialogue among all interested parties and stakeholders [26] . A first step would be for the professional colleges to create a forum to engage their memberships and encourage the exchange of views on the issue. Such an exchange could then inform the development of formal position statements on the duty to care during communicable disease outbreaks, as well as the development of clear and unambiguous guidelines regarding the professional rights and responsibilities and the ethical duties and obligations of HCPs during such outbreaks. Such statements ought to be made publicly available (e.g., prominently posted on the websites of professional health care colleges and associations) in order to encourage sustained dialogue on the issues raised by professional colleges. A next step would be to foster public debate and dialogue on the positions taken by the various health care professions. To promote this public debate, a working group at the University of Toronto Joint Centre for Bioethics has produced an ethical framework to guide preparedness planning for pandemic influenza, based in part on experiences and study of the SARS crisis [27] . The framework presents a 15-point, value-based ethical guide for pandemic planning, including the value of duty to care. This report has been made publicly available via the internet and the use of webcasting and electronic town hall meetings are being planned to facilitate an open exchange. It is of utmost importance to promote a public discourse on these issues and, most importantly, to give a voice to all those who would be directly affected by a communicable disease outbreak. Together, health care professionals and the general public should participate in discussions to determine whether and when it is legitimate for HCPs to eschew the duty to care in the face of personal risk.
In light of the recent experience of Canadian physicians, nurses, and other HCWs on the frontlines of the SARS outbreak, we submit that the Canadian health care community should lead the charge to address issues of duty to care and ethical obligations in times of public health emergencies. In place of open and honest discussion, we currently have vagueness and ambiguity. In our view, health care codes of ethics should speak specifically to this issue in order to guide professional behaviour during infectious disease outbreaks. Indeed, the time to address the ethical duty to provide care is at hand -before the arrival of the next public health emergency. Epicatechins Purified from Green Tea (Camellia sinensis) Differentially Suppress Growth of Gender-Dependent Human Cancer Cell Lines The anticancer potential of catechins derived from green tea is not well understood, in part because catechin-related growth suppression and/or apoptosis appears to vary with the type and stage of malignancy as well as with the type of catechin. This in vitro study examined the biological effects of epicatechin (EC), epigallocatechin (EGC), EC 3-gallate (ECG) and EGC 3-gallate (EGCG) in cell lines from human gender-specific cancers. Cell lines developed from organ-confined (HH870) and metastatic (DU145) prostate cancer, and from moderately (HH450) and poorly differentiated (HH639) epithelial ovarian cancer were grown with or without EC, EGC, ECG or EGCG. When untreated cells reached confluency, viability and doubling time were measured for treated and untreated cells. Whereas EC treatment reduced proliferation of HH639 cells by 50%, EGCG suppressed proliferation of all cell lines by 50%. ECG was even more potent: it inhibited DU145, HH870, HH450 and HH639 cells at concentrations of 24, 27, 29 and 30 µM, whereas EGCG inhibited DU145, HH870, HH450 and HH639 cells at concentrations 89, 45, 62 and 42 µM. When compared with EGCG, ECG more effectively suppresses the growth of prostate cancer and epithelial ovarian cancer cell lines derived from tumors of patients with different stages of disease. There is accruing evidence that green tea may have anticancer activity (1) , but the mechanisms for this action are poorly understood. Green tea is produced from the shrub Camellia sinensis (Fig. 1) ; leaves are dried but not fermented so that the green coloration attributed to polyphenols is retained. Commercially prepared green tea extracts contain $60% polyphenols (1) . These polyphenols are the source of bioflavonoids, which have strong antioxidant activity.
The major bioflavonoids in green tea are epicatechins. Like all bioflavonoids, the tea catechins have three hydrocarbon rings; hydroxyl molecules are found at the 3, 5, and 7 positions (Fig. 2) . The four major tea catechins are epicatechin (EC), EC 3-gallate (ECG), epigallocatechin (EGC) and EGC 3-gallate (EGCG). The relative proportions of EC, ECG, EGC and EGCG in non-decaffeinated green tea are 792 ± 3, 1702 ± 16, 1695 ± 1 and 8295 ± 92 mg 100 g À1 dry wt, respectively; corresponding proportions in non-decaffeinated black tea are 240 ± 1, 761 ± 4, 1116 ± 24 and 1199 ± 0.12 mg 100 g À1 dry wt (1) .
Epicatechins have apparent activity against human cancer: they reportedly may promote apoptosis (2) (3) (4) (5) (6) , arrest metastasis by inhibiting metalloproteinases (7, 8) , impair angiogenesis (9, 10) and reverse multidrug resistance (11, 12) . Although all epicatechins except EC can potentially suppress cell proliferation (13) (14) (15) (16) (17) (18) , EGCG appears the most promising and is therefore under clinical investigation in chemoprevention trials (19) . However, given the wide range in physiologic potency of the different catechins, an exclusive focus on EGCG is probably short-sighted. EGCG is reportedly more effective than EGC in decreasing the intestinal absorption of cholesterol (20) and it is the most potent catechin inhibitor of HIV-1 reverse transcriptase (21) , but ECG has the strongest collagenase inhibitory effect (22) and the highest antioxidant potential (23) . By contrast, only EGC is a potent mediator of oxidative modification and an inhibitor of xanthine oxidase during hepatic catabolism of purines (24) .
We hypothesized that the in vitro anticancer action of the various catechins varies with the type and stage of malignancy. We tested this hypothesis by examining proliferation of catechin-treated cell lines derived from organ-confined or metastatic prostate cancer (CaP) and from moderately or poorly differentiated epithelial ovarian cancer (EOC). The goal was to obtain data that would be useful for developing chemopreventive and therapeutic clinical trials in patients with gender-specific and non-specific solid tumors.
Four gender-specific human cancer cell lines were used. The HH870 androgen-receptor-negative CaP cell line was developed at Hoag Cancer Center, Newport Beach, CA, from an organ-confined primary tumor that had been resected from a 56-year-old, previously untreated Caucasian (25) . This tumor was Gleason Grade 3/4, with no evidence of vascular or perineural invasion or extracapsular extension (stage T2b). The DU145 metastatic CaP cell line (American Type Culture Collection line HTB-81) was derived from a brain lesion of 69-year-old male Caucasian. It is androgen insensitive and does not express prostate-specific antigen. Two EOC cell lines developed at Hoag Cancer Center were also used: HH639 was from a poorly differentiated clear cell, Grade 3 carcinoma in the omentum and left ovary of a 56year-old Caucasian female; HH450 was from moderately differentiated metastatic cells recovered from the abdominal fluid of a 52-year-old Asian female.
All four cell lines were cryopreserved in liquid nitrogen freezer at À70 o C. For recovery of cryopreserved cells, the vials were transferred to a 37 o C water bath for 15-30 s, further thawed at room temperature and then transferred to a 15 ml polypropylene tube with a Pasteur pipette. An aliquot of 9 ml of RPMI-9% fetal bovine serum (FBS) was added in drops. The cells were allowed to settle for 5 min and then centrifuged at 4 o C for 10 min at 300 g. Supernatant was removed, and cells were suspended in fresh RPMI, gently tapped and vortexed. Cell viability was monitored by 0.2% trypan blue dye exclusion, and cell count was determined using a hemocytometer. Cells recovered from cryovials were grown in RPMI-1640 with glutamine (Invitrogen, Carlsbad, CA) supplemented with 9% FBS, HEPES buffer, gentamycin (5 mg%) and fungizone (0.5 mg%), at 37 C in a humidified atmosphere of 5% CO 2 . Upon confluency, cells were detached with sterile EDTA-dextrose (137 mM sodium chloride, 5.4 mM potassium chloride, 5.6 mM dextrose, 0.54 mM ethylene diamine tetra acetate (EDTA), 7.1 mM sodium bicarbonate) at 37 C for 5-15 min (or $45 min for HH639), recovered with cold RPMI-1640-9% FBS and resuspended in the same medium. Use of trypsin was avoided for harvesting the cells. Cell viability and cell count were reassessed before cells were seeded in culture flasks.
All epicatechins used in this study (Fig. 2) with 50, 60 or 100 mM of each epicatechin or with no epicatechin (control) in RPMI-1640 with glutamine (Invitrogen), 9% FBS, 0.54% HEPES buffer, gentamycin (5 mg%) and fungizone (0.5 mg%).
All experiments used 25 ml sterile polystyrene tissue culture flasks with a vented blue plug seal cap (Beckton Dickinson, Franklin Lakes, NJ, Cat. No. 353107). Each flask contained stock solution with or without epicatechin in concentrations of 50 mM (five flasks for each epicatechin and five flasks for control) and 25, 75 and 100 mM (three flasks for each epicatechin and three flasks for control). Cells (0.25 · 10 6 ) suspended in 10 ml of the RPMI-1640-FBS solution described above were transferred to each flask and allowed to grow until control cells reached confluency. The cells were detached with sterile EDTA-dextrose at 37 C for 5 min, recovered with cold RPMI-1640-FBS medium and resuspended in the same medium.
Cells were counted using a hemocytometer; trypan blue dye exclusion was used to determine the number of viable versus dead cells. The interval between seeding and confluent growth of control cells was used to calculate the doubling time and the number of cell cycles. The 50% inhibitory concentration (IC50) of each catechin in each cell line was calculated using a software program (Microcal Origin Corp, OriginLab Corporation, Northampton, MA). The cells were photographed directly from the flask using light microscopy (Olympus IX-70, Japan).
Analyses of variance and Fisher's least significant difference (LSD) method were used for pairwise comparisons of values significant at the 0.05 level.
Organ-confined prostate cancer cell line HH870 and primary and metastatic epithelial ovarian cancer cell lines (HH450 and HH639) seeded (2.5 · 10 5 cells) in flasks with or without various concentrations (25, 50, 75 or 100 mM) of ECG or EGCG were photographed under a light microscope after the untreated control cells reached confluency (Fig. 3 ). Both ECG and EGCG significantly affected the density of each cell line at or above 75 mM. The decrease in cell density at higher concentrations is much pronounced for ECG than for EGCG, a finding significant considering recommendations of clinical trials with EGCG (19) .
The mean density or viable cell number (in millions) (n ¼5 per treatment) of different cell lines was examined with or without catechins (50 mM) (Fig. 4) . The cell density was measured when growth of untreated cells reached confluency. Statistical analysis by ANOVA as well as by pairwise comparison showed that both ECG and EGCG significantly affected the cell density. ECG decreased the cell density of prostate cancer cells DU145, HH870 and ovarian cancer cell line HH639 more potently than EGCG. But EGCG inhibited the growth of ovarian cancer cell line HH450 better than ECG, suggesting the need to determine relative efficacy of ECG and EGCG in clinical trials for different cancers.
Tumor Cell Doubling Time: ECG versus EGCG Figure 5 shows the influence of the four epicatechins on cell doubling time. ECG and/or EGCG prolonged the doubling (14) EGC and ECG inhibited the growth of a human lung cancer cell line, PC-9 cells as potently as did EGCG, but EC did not show significant growth inhibition. The mechanism of growth inhibition by EGCG was studied in relation to cell-cycle regulation. EGCG (50 and 100 mM) increased the percentages of cells in the G
The relative cytotoxicity (CTX) of ECG to carcinoma HSC-2 cells and normal HGF-2 fibroblasts cells from the human oral cavity, as compared with other polyphenols in tea, was evaluated. For the HSC-2 carcinoma cells, ECG, CG and EGCG grouped as highly toxic, EGC as moderately toxic, and C and EC as least toxic. For the HGF-2 fibroblasts, ECG and CG grouped as highly toxic, EGCG as moderately toxic, and EGC, C and EC as least toxic. The CTX effects of the polyphenols were more pronounced to the carcinoma, than to the normal, cells. Table 1 summarizes the effects of EC, ECG, EGC and EGCG on viability, doubling time and cycling of the four cell lines. Untreated cells from each line reached confluency in about 2.5 cell cycles. EC did not affect the proliferation of DU145, HH870 or HH450 cells but it reduced the proliferation of HH639 cells by half (P < 0.05) and prevented their confluent growth (Table 1) . EGC did not affect the proliferation of any cell line (Table 1) , whereas EGCG arrested proliferation of all four lines. ECG, followed by EGCG, was the most potent inhibitor of cell growth and cycling.
Proliferation of each cell line (n ¼ 3 per treatment) was monitored with or without ECG or EGCG at concentrations of 0, 25, 50, 75 and 100 mM. The dosimetric results plotted in Fig. 6 shows concentration-dependent suppression of cell growth by ECG and EGCG. The suppressive effect on cell density was striking at higher concentrations of ECG and EGCG. ECG was a more potent inhibitor of cell growth than EGCG. At 25 mM of EGCG, cell numbers for HH870 and DU145 were significantly higher than control values. Based on the results plotted in Fig. 6 , IC50 values were calculated. The IC50 values are 24-30 mM for ECG, versus 42-89 mM for EGCG (Table 2 ). ECG suppressed growth at all higher concentrations tested (Fig. 6) , whereas EGCG significantly (P < 0.05) enhanced proliferation of CaP cells at 25 mM, a finding relevant to chemoprevention trials with EGCG only.
Green tea is widely consumed in Japan and China and its polyphenolic components have a chemopreventive effect against cancer in vitro and in vivo (39) . A cup of green tea contains 100-150 mg catechins, of which 8% are EC, 15% are EGC, 15% are ECG and 50% are EGCG (40) . Although numerous investigations have shown the role of EGCG in cancer chemoprevention, only a few studies have attempted to compare the relative antitumor efficacy of all four catechins (Table 3) . When we used a systematic approach to assess the effect of various catechins on cell lines derived from gender-based cancers, we found that each catechin's antitumor activity depended on the type of tumor. EGCG was not always the most potent chemopreventive agent.
Most of the earlier literature (Table 3) indicates that EGCG is the most potent growth inhibitor of cell lines from glioblastoma, melanoma and cancers of the breast, colon, lung, prostate (androgen-receptor-positive), pancreas, liver and mouth. EGCG prevents proliferation of DU145 cells by arresting the cell cycle at G 0 /G 1 -phase (19) . Gupta and others (26) have documented that G 0 /G 1 -phase arrest is independent of p53 mutation, and EGCG treatment of DU145 induces the cyclin kinase inhibitor WAF1/p21. These observations suggest that EGCG imposes a cell-cycle checkpoint (19) . However, our results showed that ECG may be more potent than EGCG for inhibition of primary and metastatic CaP and EOC cells (Fig. 4, Tables 1 and 2) . ECG significantly reduced cell proliferation (Table 1, Figs 2 and 3) and increased mean doubling time (Table 1, Fig. 4) .
The in vitro effect of chemopreventive agents can be studied when tumor cells are in a matrix (1, 4, 27) or in a suspension (28, 29) . We used the suspension method because it exposes the entire cell surface to the chemotherapeutic agent. Our findings confirm an earlier report that used the matrix method to show that ECG is more potent than EGCG in suppressing the proliferation of DU145 CaP cells (4) . Thus reported differences in the relative efficacy of different catechins may not be due to differences in methodology.
Not all tumor cells are killed by catechins. In our study, ECG (50 mM) induced death of most but not all HH639 cells. Doubling ECG's IC50 concentration might increase the tumor kill rate if ECG does not epimerize to CG. Our in vitro dose of 100 mM is equivalent to 29 mg (EC/EGC) to 45 mg (EGCG/ ECG), far less than the 100-150 mg (50% of which is EGCG) in one cup of green tea. However, Lee et al. (41) reported that plasma levels of EGCG and EGC in healthy volunteers increased to 78 and 223 ng ml À1 , respectively, 20 min after drinking brewed green tea (1.2 g of tea solids in 200 ml hot water). This suggests that drinking more than 10 cups of green tea may be necessary to maintain a plasma concentration of EGCG equivalent to that used in vitro by a dose of 50 mM or 22.5 mg. Kaegi (42) suggested a daily intake of 13 cups of green tea as a chemopreventive measure. Because this level of tea consumption is impractically high, chemoprevention of cancer with catechins may require administration of the appropriate catechin in a purified form.
In conclusion it may be stated that both green and black tea polyphenols are important components of antitumor aspect of complementary and alternative medicine (CAM), which play a significant role in the American health care system and in patients who suffer from chronic problems (43) . While green tea catechin gallates such as EGCG and ECG possess potent antitumor activities, their epimers, commonly found in black tea, act as potent inhibitor of proteases involved in replication of viruses, including coronoviruses (44) . There is a need to understand preventive and therapeutic potential of catechin gallates from both green and black teas. We are currently designing a phase I chemopreventive study to examine the effects of purified EGCG and ECG in patients who have been chosen observational management of organ-confined prostate cancer. Markers of exacerbation severity in chronic obstructive pulmonary disease BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) can experience 'exacerbations' of their conditions. An exacerbation is an event defined in terms of subjective descriptors or symptoms, namely dyspnoea, cough and sputum that worsen sufficiently to warrant a change in medical management. There is a need for reliable markers that reflect the pathological mechanisms that underlie exacerbation severity and that can be used as a surrogate to assess treatment effects in clinical studies. Little is known as to how existing study variables and suggested markers change in both the stable and exacerbation phases of COPD. In an attempt to find the best surrogates for exacerbations, we have reviewed the literature to identify which of these markers change in a consistent manner with the severity of the exacerbation event. METHODS: We have searched standard databases between 1966 to July 2004 using major keywords and terms. Studies that provided demographics, spirometry, potential markers, and clear eligibility criteria were included in this study. Central tendencies and dispersions for all the variables and markers reported and collected by us were first tabulated according to sample size and ATS/ERS 2004 Exacerbation Severity Levels I to III criteria. Due to the possible similarity of patients in Levels II and III, the data was also redefined into categories of exacerbations, namely out-patient (Level I) and in-patient (Levels II & III combined). For both approaches, we performed a fixed effect meta-analysis on each of the reported variables. RESULTS: We included a total of 268 studies reported between 1979 to July 2004. These studies investigated 142,407 patients with COPD. Arterial carbon dioxide tension and breathing rate were statistically different between all levels of exacerbation severity and between in out- and in-patient settings. Most other measures showed weak relationships with either level or setting, or they had insufficient data to permit meta-analysis. CONCLUSION: Arterial carbon dioxide and breathing rate varied in a consistent manner with exacerbation severity and patient setting. Many other measures showed weak correlations that should be further explored in future longitudinal studies or assessed using suggested mathematical modelling techniques. Chronic obstructive pulmonary disease (COPD) is a respiratory disease characterized by an airflow limitation and inflammation of the lower airways [1] . As the disease worsens, some patients experience 'exacerbations' of their principal symptoms of dyspnoea, cough and sputum. These exacerbations frequently result in a visit to a general practitioner's office or to a local hospital for treatment. Exacerbations occur in COPD patients at a median of three times a year with half of them being unreported [2] [3] [4] . The heterogeneity of COPD exacerbations make them difficult to define, classify and manage due to their range of symptoms, varied treatment requirements, seasonal occurrence, and ambiguous aetiology [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] .
To address this problem, attempts have been made to develop a consensus definition for COPD exacerbations [15] . Recently, the American Thoracic Society (ATS) and European Respiratory Society (ERS) adopted the following definition: 'an event in the natural course of the disease that is characterised by a change in the patient's baseline dyspnea, cough and sputum beyond day-to-day variability sufficient to warrant a change in management' [1] .
The severity of an exacerbation has been also difficult to classify despite the various schemes that have been proposed to deal with this issue [4, [15] [16] [17] . The ATS and ERS have also jointly suggested a classification based upon severity and the type of medical management used, i.e., Exacerbation Level I is home treatment, Level II is hospitalization, and Level III is specialised care [1] . The aim of this scheme is to improve the existing management of exacerbations and to serve as an aid in the assessment of treatment efficacy. Different operational definitions for COPD exacerbations have been proposed in the past and these have helped determine their relative importance, in particular their relationship to COPD progression [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] . However, these definitions have relied primarily on symptoms, and this along with the absence of a standard classification for the degree of symptom severity, has delayed the development of new therapies for this condition. The current therapies for exacerbations have been evaluated based on their ability to reduce symptoms, and to improve a patient's forced expiratory volume in one second (FEV 1 ) since the latter is strongly correlated with COPD mortality. However, FEV 1 does not discriminate well between the stable and exacerbative states of COPD, particularly during the later stages of this disease. Hence, the development of biological markers, or biomarkers that are more sensitive and specific to the severity of COPD exacerbations would provide investigators with new insights and directions for further research.
At this time, only a few clinical variables or inflammatory mediators have been shown to be associated with COPD exacerbations and their related morbidity and mortality. Some of those include: age [18] [19] [20] ; FEV 1 , forced vital capacity and peak expired flow [19, 21, 22] ; body mass index [20] ; albumin [20, 22, 23] ; sodium [23] ; pH [24, 25] ; eosinophils [26] [27] [28] [29] ; interleukins 6 and 8 [29] [30] [31] [32] ; fibrinogen [31] ; and C-reactive protein [33] . Significant clinical events such as the number of exacerbations per year, the number of hospital admissions per year, time to relapses, and days in hospital have been regarded as useful measures in clinical studies designed to assess drug efficacy and cost-effectiveness as well as to standardize existing hospital support programs for COPD [34] [35] [36] [37] [38] [39] . However, it is not known how these measures change with increasing severity of COPD exacerbations. Therefore, we have surveyed the medical literature to identify which of the commonly accepted variables and suggested markers for COPD exacerbations change according to the ATS/ERS' levels of exacerbation severity. The long-term aim of our work is to assess the sensitivity and specificity of potential markers for use in future COPD studies as well as to determine how such markers can be further studied and fully integrated into the development of new drugs for COPD.
We searched standard databases since 1966 using medical search headings and related terms as obtained from major consensus documents related to COPD exacerbations. The major keywords were 'exacerbation', 'unstable', 'acute', 'bronchitis', and variants of the term 'COPD'. This phase of our search retrieved a total of 843 citations. For these citations, we read the title and abstract of each citation so as to exclude citations that concerned exacerbations of coronary artery disease, myocardial infarction, cystic fibrosis, asthma, pulmonary emboli, and community pneumonia. Citations for case studies, letters, reviews, meta-analyses, and animal studies were also excluded.
After this initial screening, we identified 387 citations to papers that were of possible interest. We retrieved the original articles in electronic and hard copy forms, and then critically read each article. As a result of this step, we arrived at a total of 268 studies in our final review and analyses. We selected these studies based on the availability of demographics, spirometry, clear study eligibility criteria, and the potential markers being used to assess exacerbations.
The objectives of this literature review and data analyses were to determine which of the baseline measures com-monly used in COPD exacerbation studies change with the extent of the exacerbation and disease severity, and to determine whether COPD exacerbations can be modelled as 'events' or 'time-to-event' in future investigations.
Initially, we considered various exacerbation definitions and classification schemes, in particular, those suggested by Rodriguez-Roisin [15] as well as those described by Pauwels and colleagues [17] . However, we determined that the ATS/ERS' operational classification of exacerbation severity [1] was the most sensible and feasible system for systematically assessing the patient baseline characteristics and biomarker information from the majority of published studies. We therefore used this classification scheme and the related clinical history, physical findings and diagnostic procedures for managing exacerbations to perform our data abstraction. From each study, we retrieved the reported demographics, spirometry, smoking status, clinical, cytological and biochemical variables as well as suggested markers of the severity of the exacerbation at baseline conditions, i.e., immediately prior to, or during the exacerbation event but before the time in which the intervention of interest was investigated (Table 1 ). Whenever such variables were measured in stable conditions, we also abstracted this information. For each study, we noted the type of definition used to define an exacerbation such as symptom-or event-based as well as the research question asked, the experimental design used, any sponsorship, and the presence or absence of data from individual study patients. Data was then further organized according to sample size and smoking status when available. Cytological and biochemical data were also classified according to their collection methods. These included sputum induction, bronchial biopsy, bronchoalveolar lavage (BAL), exhaled breath sampling, and blood sampling.
We were also aware of the possibility that for some study groups in severity Levels II and III (as per the ATS/ERS criteria) included in this review may have experienced a similar quality of care or medical management that was not reported adequately in the original publication. In attempt to correct for this problem, we combined the exacerbation data from Levels II and III into an 'in-patient' category and then compared it to Level I that we regarded as the 'out-patient' category.
We collected and calculated study means, medians, standard errors, standard deviations, 95% confidence interval, and inter-quartile ranges using the statistical algorithms in Microsoft Excel 2002. We then conducted fixed effect meta-analyses to obtain mean point estimates, 95% confidence intervals, and two standard deviations for each exacerbation level [40] . Exacerbation Severity Levels I and II, II and III, and I and III were each compared using a twotailed Z-test. The alpha level of p < 0.05 was adjusted for multiple testing according to the Bonferroni correction procedure [41] . In the event that a specific exacerbation severity level had a large number of studies in which only median data were available, the data were considered to be normally distributed and medians were treated as means. Since many studies did not publish data for individual patients, we were limited in addressing non-normality in the data by using a log 10 -transformation.
We again performed a fixed effect meta-analysis to obtain mean point estimates, 95% confidence intervals, and two standard deviations for in-patient and out-patient categories of each measure. We then compared each category using a two-tailed Z-test and a p-value of 0.05.
Our search strategy yielded 268 suitable studies that met our selection criteria. These studies were published between 1979 and July 2004 -Week 2. (The references for these studies can be found at the LACDR Division of Pharmacology website [42] ). The total number of study subjects included in this review was 142,407. Of this group, 18% fell in Exacerbation Severity Level I, 78% in Level II, and 4% in Level III. When we re-analysed the data according to out-or in-patient settings, 18% were out-patients and 82% in-patients.
Meta-analyses of typical study demographics showed that there was significant overlap in 95% confidence intervals and study data distributions for the three exacerbation severity levels except for age where study patients in Level II had a mean age of 64.2 years (95% confidence interval (CI): 62.9 to 65.5 years) compared to 68.0 years (95% CI: 65.9 to 70.1 years) for patients in Level III (p = 0.002) ( Table 2 ). When the demographics were re-analyzed according to patient settings, we determined that only body mass index was statistically different between the out-patient setting (mean point estimate: 26.2 kg/m 2 ; 95% CI: 23.8 to 28.7 kg/m 2 ) and the in-patient setting (mean point estimate: 23.4 kg/m 2 ; 95% CI: 22.5 to 24.3 kg/m 2 ) (p = 0.038) ( Table 3) .
The spirometry measures Forced Expired Volume in 1 Second (FEV 1 ) and Forced Vital Capacity (FVC), both in percent predicted, decreased from Exacerbation Levels I to II (p < 0.017) but remained unchanged from Levels II to III ( Figure 1A and 1C, respectively). However, when Levels II and III were combined to create an 'in-patient' category for each of these variables, there was a statistically signifi-Respiratory Research 2006, 7:74 http://respiratory-research.com/content/7/1/74 cant decrease for the in-patients versus the out-patients (p < 0.05) ( Figure 1B and 1D, respectively). We also observed the same trend for FEV 1 /FVC (Figure 2A and 2B ). For all other spirometry measures, there were too few studies available in Level III for meta-analysis.
We found for smoking that pack years increased with exacerbation severity, but only Levels I and II were statistically different (p = 0.015) ( Figure 2C ). When we compared pack years between patient settings, it was statistically higher for the in-patients than the out-patients (p = 0.010) ( Figure 2D ).
In terms of the hemodynamic measures, only heart rate showed a statistically significant difference being higher in Level II than Level I (p = 0.014) with no difference Many study variables were measured at or around the time of the exacerbation. If these variables were measured in the stable condition of these COPD patients, i.e., measurements were taken weeks or months prior to the exacerbation, then these were also obtained.
between Levels II and III ( Figure 3A ). Heart rates were also higher for in-patients than out-patients (p = 0.011) (Figure 3B ).
The clinical measures of dyspnoea, i.e., the breathing rate ( Figure 3C ) and Borg dyspnoea score, tended to increase from Levels I to II and then decrease from Levels II to III. However, only breathing rate demonstrated clear statistical differences between the three levels (p < 0.017). Only Levels II and III of the Borg Dyspnoea Score were statistically different (p < 0.001); a statistical comparison of these levels with Level I was not possible due to lack of data. When patient settings were compared, only breathing rate showed a clear statistical difference being statistically lower for in-patients than out-patients (p = 0.003) ( Figure 3D ).
Exacerbation Levels II and III were statistically different with respect to pH (p = 0.003) and bicarbonate (p = 0.002) in that pH decreased from Level II to III whereas bicarbonate increased. However, there was insufficient Level I data for each variable to allow for statistical comparisons with the other Levels. There was also insufficient data available to compare out-patients with in-patients.
In terms of blood gas measures studied, only arterial carbon dioxide tension (PaCO 2 ) showed a statistically significant increase with increasing exacerbation severity (p < 0.017) ( Figure 4A ) as well as out-versus in-patients (p < 0.05) ( Figure 4B ). In the case of oxygen saturation, it gradually decreased with increasing exacerbation severity with statistically significant differences between Levels I and II (p < 0.001) as well as Levels I and III (p = 0.011) ( Figure 4C ). It also decreased going from an out-patient to an inpatient setting (P < 0.001) ( Figure 4D ).
The six minute walking distance challenge test seemed to show a decreasing trend with increasing exacerbation severity but such changes did not reach statistical significance. This was also the case when the out-and in-patients were compared. Many other variables related to spirometry, respiratory status, exacerbation and hospital event categories also did not change significantly with exacerbation severity or out-and in-patients (See additional file 1). There was not enough data in the bacteriology and virology categories to permit any meta-analyses. Of the 268 studies sampled, only half contained data about the biochemical variables.
We conducted this review of the COPD exacerbation literature to determine which commonly-accepted baseline variables and suggested markers changed in a consistent manner with the severity of COPD exacerbations. As our index of COPD severity, we used the recently published ATS/ERS operational classification of exacerbation severity for medical management. This is because most of the published literature rarely provides sufficient details to characterise the severity of a patient's exacerbation. In addition, we also analyzed the same data according to out-and in-patient settings so as to account for possible overlaps in medical management between Levels II and III but were not reported in the original publication.
The long-term aim of our work is to improve the quality and applicability of exacerbation management through the identification of sensitive and specific markers that can be used for the assessment of treatment effects. This review identified a few potential markers of exacerbation severity.
When we assessed the spirometry measures FEV 1 and FVC in % predicted, as well as FEV 1 /FVC, we observed statistically significant differences with exacerbation severity, and between out-and in-patients ( Figures 1A-D and 2A -B). One draw-back was the paucity of such information in Level III studies. This confirms the clinical situation that as exacerbations worsen and more specialised care is required, spirometry measurements are less likely under baseline conditions or during an exacerbation [14] . Thus, such data is rare in many published studies.
The number of smoking-related pack years increased with exacerbation severity and showed a clear difference between out-and in-patient settings ( Figures 2C and 2D) , a finding that is consistent with the idea that the more a COPD patient smokes, and for longer, the higher the likelihood that COPD exacerbations will be more severe.
According to the mean point estimates obtained in this In-patient (N=81;n=5768) PaCO2 (mmHg) * B study, COPD patients with 40 to 60 pack-years of smoking will experience an increase in the severity of COPD exacerbations. However, our conclusion regarding this finding is limited by there being data from only two studies at Level III.
Although heart rate varied little between Exacerbation Levels II to III, it is important to note that it was substantially elevated in patients ( Figure 3A ) with the clearest difference being between in-and out-patients. This is possibly associated with the anxiety and dyspnea that experienced when an exacerbation occurs. The increase in heart rate of course increases the oxygen requirements of the heart. The increased heart rate may also be the result of underlying cardiovascular disease that is more prominent in severe COPD patients [43] .
The relationship of pH and bicarbonate to exacerbation severity are consistent with the signs of respiratory acidosis evident in COPD patients with exacerbations [1, 24, 25] . However, due to the shortage of data in Level I, proper statistical conclusions about each of these variables are difficult to make. In relation to this, breathing rate significantly increased from Levels I to II and then decreased from Levels II to III ( Figure 3C ). The first observation may reflect components of the exacerbation episode (i.e., anxiety and dyspnea) as well as the physiological need to breathe more to maintain adequate blood gas levels. The reduction at Level III possibly reflects the results of the specialized care where patients are given ventilatory support so as to return the breathing rate to normal. The Borg Dyspnea Score showed the same trend as breathing rate, although insufficient data in Level I did not allow for further comparisons. When out-and inpatient data were compared for each of these variables, only breathing rate demonstrated a clear statistical difference ( Figure 3D ). The Borg Dyspnoea Score on the other hand did not have enough studies in the out-patient category to perform any statistical test. Overall, the observed trends were consistent with the fact that management of dyspnoea is one of the main factors generating the high hospital costs associated with COPD exacerbations [44] . In keeping with the direct measures of dyspnoea, arterial carbon dioxide tension showed a clear relationship with exacerbation severity and patient management settings ( Figures 4A and 4B ) that is consistent with the conclusions reported in the medical literature [20, [45] [46] [47] . Arterial oxygen tension in contrast did not change with exacerbation severity or patient setting. Possibly this lack of correlation reflects the immediate administration of supplemental oxygen given to hypoxaemic patients in a hospital setting. There was however a decreasing trend in oxygen saturation with increasing exacerbation severity and clear differences between out-and in-patient settings ( Figures 4C and 4D ) that are consistent with the present thinking on blood gas changes.
Most of the other commonly accepted measures and suggested biomarkers poorly reflected exacerbation severity, or the fact that there was not sufficient data to undertake a meta-analysis (See additional file 1). This finding recalls a 2001 US Department of Health and Human Services report on exacerbation treatment outcomes from over 200 randomised controlled trials [14] . The aim of that study was to create new guidelines to improve the management of COPD exacerbations. That study also concluded that the current literature was limited in terms of the number of studies and the amount of detail available as well as the reliability and accuracy of the clinical assessments used to discriminate between COPD exacerbations and other causes of worsening respiratory status. Thus, our observations agree with previous observations regarding the assessment of the unstable COPD literature.
As previously discussed, most of the studies used for this review were predominately with hospitalized patients (Level II). However, most COPD occurs in an out-patient setting (Level I) [48] [49] [50] [51] [52] [53] . This has implications for our study since the latter population was poorly represented.
Our basic categorisation was according to the ATS/ERS' operational scheme for classifying the severity of COPD exacerbations as well as to out-and in-patient categories. To our knowledge, we are the first to undertake this type of literature review and thus we were faced with a lack of consistency in the definition of exacerbations as used in the various studies. We tried to overcome this difficulty by selecting and ranking clinical studies so as to improve the comparability of subjects between studies.
We were also aware that the clinical studies we analysed differed with respect to which comorbidities or identifiable causes for exacerbations were reported. Most patients were elderly and therefore were more likely to be suffering from one or more co-existing diseases such as asthma or cardiovascular disease. Such co-morbidity makes interpretation of our findings more difficult with respect to the true causes of exacerbations. If their aetiology could be determined, then susceptible patients such as those in Level I could be identified and new treatments developed to help prevent their onset and related hospital costs.
Finally, the compatibility between the studies of COPD exacerbation that we analysed may have been limited by substantial variations in the time and location of studies. Exacerbations are more likely in summer [5] but many studies failed to report the time of year or the time period for study implementation. Thus, seasonal effects, combined with the low incidence of exacerbations per patient, could represent an inherent bias. In addition, different institutions probably had different standards with respect to diagnosis and management of COPD exacerbations when these studies were performed. Such variations may also explain any observed inconsistencies in our findings. However, we attempted to overcome this possible bias in Exacerbation Levels II and III by the subsequent re-analysis of this data on the basis of out-patient and in-patient settings.
As observed in The additional online file, there was a scarcity of information particularly for biomarkers at different exacerbation levels. It is also unclear to us whether any of the variables that changed with exacerbation severity are causally-related. Hence, longitudinal studies and/or less restrictive eligibility criteria would be needed to address all these questions. One difficulty in tackling such problems is the enormous amount of time and expense involved in implementing such studies. In addition, the current methods for data analysis in clinical studies have limitations imposed by the assessment of the reduction in frequency or total suppression of exacerbation episodes (i.e. rare event or "non-event").
To overcome these drawbacks and obtain more accurate evaluation of treatment effect on COPD exacerbations, alternative analytical methods based, for example, on predictive mathematical models such as hidden Markov chains or Bayesian forecasting should be tried. Such models can characterise and predict rare events without undertaking a full-scale, long-term longitudinal study. This approach to predicting rare events has been used previously in studies of migraine, epilepsy and various cardiovascular diseases where the size of treatment effect is measured in terms of a reduction in the frequency of the repetition of an event within a given probability or within a given time period [54, 55] . One example of a mathematical model development includes the use of a Markov model to predict COPD exacerbation rates in a clinical trial of the inhaled anticholinergic bronchodilator tiotropium [56] . In this example, the model was developed on the basis of prior knowledge of the exacerbation rate as estimated from meta-analyses of randomised controlled trial data. This gave the probabilities for COPD exacerbations for different stages of COPD. In another study, a proportional hazards model was used to identify risk factors for COPD patients hospitalised due to an exacerbation [44] . The current ATS/ERS guidelines for exacerbations do not consider the implications of using probabilistic models as a means of assessing the severity of COPD exacerbations or the effect of treatment [1] . A modelling approach may offer new insights into which variables related to COPD exacerbations should be investigated.

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