Markers of exacerbation severity in chronic obstructive pulmonary disease

Abstract

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.

Figure 1

Fixed Effect Meta-Analysis Results of Selected Spirometry Variables. Graphs displayed are: A) FEV₁ % Predicted (COPD Exacerbation Severity Levels I to III); B) FEV₁ % Predicted (Out- versus In-patient Setting); C) FVC % Predicted (Levels I to III); and D) FVC % Predicted (Out- versus In-patient Setting). For each spirometry variable, the point estimates (point), 95% confidence intervals (box), and two standard deviations (bars) are presented for Levels I to III and out- & in-patient settings. 'N' signifies the total studies and 'n' is the total subjects. P < 0.017 is indicated for statistical comparisons of Level I versus II (*), II versus III (†), and I versus III (#) as well as P < 0.05 for comparison of out- versus in-patient setting (*).

Figure 2

Fixed Effect Meta-Analysis Results of Selected Clinical Variables. Graphs displayed are: A) FEV₁/FVC Ratio (Exacerbation Severity Levels I to III); B) FEV₁/FVC Ratio (Out- versus In-patient Setting); C) Pack Years (Levels I to III); and D) Pack Years (Out- versus In-patient Setting). For each clinical variable, the point estimates (point), 95% confidence intervals (box), and two standard deviations (bars) are presented for Levels I to III and out- & in-patient settings. 'N' signifies the total studies and 'n' is the total subjects. P < 0.017 is indicated for statistical comparisons of Level I versus II (*), II versus III (†), and I versus III (#) as well as P < 0.05 for comparison of out- versus in-patient setting (*).

Figure 3

Fixed Effect Meta-Analysis Results of Selected Clinical Variables. Graphs displayed are: A) Heart Rate (Exacerbation Severity Levels I to III); B) Heart Rate (Out- versus In-patient Setting); C) Breathing Rate (Levels I to III); and D) Breathing Rate (Out- versus In-patient Setting). For each clinical variable, the point estimates (point), 95% confidence intervals (box), and two standard deviations (bars) are presented for Levels I to III and out- & in-patient settings. 'N' signifies the total studies and 'n' is the total subjects. P < 0.017 is indicated for statistical comparisons of Level I versus II (*), II versus III (†), and I versus III (#) as well as P < 0.05 for comparison of out- versus in-patient setting (*).

Figure 4

Fixed Effect Meta-Analysis Results of Selected Clinical Variables. Graphs displayed are: A) Arterial Carbon Dioxide Tension, PaCO₂(Exacerbation Severity Levels I to III); B) PaCO₂ (Out- versus In-patient Setting); C) Percent Oxygen Saturation – Arterial & Pulse Measurements Combined (Levels I to III); and D) Percent Oxygen Saturation – Arterial & Pulse Measurements Combined (Out- versus In-patient Setting). For each clinical variable, the point estimates (point), 95% confidence intervals (box), and two standard deviations (bars) are presented for Levels I to III and out- & in-patient settings. 'N' signifies the total studies and 'n' is the total subjects. P < 0.017 is indicated for statistical comparisons of Level I versus II (*), II versus III (†), and I versus III (#) as well as P < 0.05 for comparison of out- versus in-patient setting (*).