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Keywords:

  • acute exacerbation;
  • acute-phase reactant;
  • chronic obstructive pulmonary disease;
  • cytokine;
  • inflammation

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Background and objective:  The temporal profile of inflammatory markers during acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and their relationship to clinical response are not well characterized. The aim was to assess the changes in levels of inflammatory markers in AECOPD and correlate these with clinical and laboratory indices of recovery.

Methods:  Serum levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen were measured in patients with AECOPD within 24 h of hospitalization and pre-discharge (stable state).

Results:  Ninety-seven patients were evaluated (79 males; mean (SD) age, 61.4 (10.3) years). Eighty eight (90.7%) were current or former smokers, with a median consumption of 15 (0–75) packs/year. The median duration of COPD was 8 (2–25) years. Forty-six patients (56.9%) required mechanical ventilation for a median of 5 days (1–34) while in hospital. The median duration of hospital stay was 13 days (1–77). At reassessment before planned discharge, the levels of dyspnoea, leucocyte counts, erythrocyte sedimentation rate, creatinine, partial pressure of oxygen, and albumin normalized. The levels of CRP, IL-6 and fibrinogen reduced significantly but did not reach the normal range. Changes in IL-6 and fibrinogen levels correlated significantly with the acute physiologic assessment and chronic health evaluation II score, smoking history, blood pressure and leucocyte counts. Baseline IL-6 and fibrinogen levels significantly predicted a prolonged duration of mechanical ventilation.

Conclusions:  During AECOPD, the inflammatory response lags behind clinical and biochemical improvement. Fibrinogen and IL-6 are potentially useful markers for monitoring clinical response following an acute episode.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are important events and represent a major societal, financial and emotional burden for these patients.1 Recently, the role of airway and systemic inflammation in chronic obstructive pulmonary disease (COPD) has been explored by measuring various inflammatory markers. During AECOPD, increased levels of interleukin (IL)-6, IL-8, tumour necrosis factor-α, myeloperoxidase, neutrophil elastase and leukotriene B4 have been measured in sputum, suggesting an inflammatory burst,2,3 which has also been detected in exhaled breath condensate.4 In addition, the identification of these cytokines in plasma/serum of COPD patients strongly suggests that the local inflammatory response communicates with the systemic circulation through these mediators.

During the last decade, several studies investigating systemic manifestations of COPD have also reported enhanced levels of several circulating inflammatory mediators, including acute-phase reactants and cytokines.5–7 However, most of these were follow-up cohort studies that attempted to demonstrate changes in the levels of these mediators between the stable state and episodes of exacerbation. The temporal profile of inflammatory markers during an acute episode and their relationship to clinical responses is not well characterized. We hypothesized that acute exacerbations are associated with greater inflammatory responses that are reduced with clinical improvement. This study was therefore designed with the following objectives: (i) to study the temporal profile of certain inflammatory markers in patients with AECOPD; and (ii) to study the concordance, if any, between the subsidence of inflammation and other clinical and laboratory indices of recovery.

METHODS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Patient recruitment

This was a prospective observational study of consecutive patients admitted with a diagnosis of AECOPD to the medical wards and intensive care unit of the All India Institute of Medical Sciences, New Delhi (a tertiary care centre in north India), between February 2007 and March 2009. Patients requiring admission to hospital, according to the guidelines of the American Thoracic Society/European Respiratory Society Consensus statement, were included in the study.8 The diagnosis of AECOPD was based on a history of acute and sustained worsening of the patient's condition from a stable state and exceeding normal day-to-day variation, thereby necessitating a change in regular medication.9 Exacerbations were further categorized into three types according to an increase in the severity of at least one of the following symptoms: dyspnoea; increased sputum volume and sputum purulence severe enough to warrant hospital admission. Type 1 exacerbations were the most severe and were defined by the presence of all three symptoms; type 2 exacerbations involved two of the three symptoms and type 3 exacerbations involved one of the three symptoms, in addition to at least one of the following: an upper respiratory tract infection lasting 5 days, fever or increased wheezing.10 Patients with COPD who were admitted with any other primary diagnosis, including acute coronary syndrome, congestive heart failure, tuberculosis, tropical infections, bronchiectasis or multi-organ failure were excluded. Patients provided informed consent, and approval for the study was obtained from the Institute Ethics Review Board.

Clinical variables

Detailed clinical and demographic data were obtained at the time of admission. Duration of disease as determined by the total duration of symptoms, history of previous hospital admissions, history of prior mechanical ventilation unrelated to surgery, and evidence of cor pulmonale based on jugular venous distension, pedal oedema, loud pulmonary heart sounds and an electrocardiogram was recorded. Active smokers were defined as those who had smoked within the past 6 months. The presence of comorbidities such as diabetes mellitus, hypertension, ischaemic heart disease, carcinoma of the lung and a past history of pulmonary tuberculosis was noted. To quantify comorbidities, the Charlson comorbidity index11,12 was calculated using these variables, but excluding COPD. Clinical parameters, including heart rate, respiratory rate and mean blood pressure were recorded. The Glasgow coma scale and the acute physiologic assessment and chronic health evaluation II score were recorded at the time of admission. Baseline arterial blood gas analyses and chest radiography were performed for all patients, and respiratory secretions were subjected to Gram staining and bacterial culture. Laboratory measurements included blood haemoglobin concentration, total leucocyte counts, renal and hepatic function tests, and serum sodium and potassium concentrations.

Patients were managed by the treating medical unit, with regular nebulized bronchodilators, corticosteroids and antibiotics, according to a standard hospital protocol. Mechanical ventilation was instituted by the treating physician for indications such as respiratory arrest, deterioration in level of consciousness and increasing partial pressure of arterial carbon dioxide despite maximal pharmacological treatment. Non-invasive ventilation was used initially whenever possible and indicated. Decisions regarding admission or transfer to intensive care unit were taken by the treating unit. Complications during the hospital stay, such as pneumothorax, were recorded. All patients were followed to discharge or death.

Measurement of inflammatory mediators

Within 24 h of admission to hospital, 4–5 mL of blood was taken from an antecubital vein without venestasis and divided equally among vacuum collection tubes containing heparin and plain vials. The blood samples were centrifuged at 1207 g for 10 min at ambient temperature. Plasma/serum was separated and immediately stored in aliquots at −80°C until the immunoassays were performed. IL-6 and C-reactive protein (CRP) were measured in serum, whereas fibrinogen was measured in plasma. For CRP measurements, serum was diluted 100-fold and for fibrinogen measurements, plasma was diluted 1:10 000 as per the manufacturers' instructions. Mediators were measured using commercially available enzyme-linked immunosorbent assay kits for IL-6 (Immunotech, Marseille, France), CRP (DRG International Inc., Mountainside, NJ, USA) and fibrinogen (Hyphen BioMed, Andrésy, France). Assays were performed in triplicate and were found to be reproducible. The analyses were performed by blinded investigators who had no information relating to the patients being studied. Changes in mediator levels were evaluated and correlated with clinical and laboratory assessments of response.

Statistical analyses

The data were entered into an Excel spreadsheet and analysed using STATA version 10.0 software (StataCorp, College Station, TX, USA). Numerical data are expressed as means (SD) or medians (range). Differences in laboratory parameters, including levels of inflammatory markers, were assessed for statistical significance using analysis of variance and the Wilcoxon sign rank test for continuous variables, and Pearson's chi-square test and Fisher's exact test for nominal variables. Linear and multiple regression was used and partial correlation coefficients were calculated for the correlations between differences in CRP, fibrinogen and IL-6 levels, and clinical variables, after adjustment for pack-years of smoking.

RESULTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

A total of 97 patients were evaluated (79 males; mean (SD) age, 61.4 (10.3) years). Eighty eight (90.7%) were current or former smokers, with a median (range) consumption of 15 (0 to 75) pack-years, duration of COPD of 8 years (range 2 to 25) and duration of current symptoms of 5 days (range 1 to 30). The mean (SD) Charlson index was 1.2 (0.5). Sixty-four per cent of patients had associated comorbidities, with hypertension being the commonest (45%). Inhaled bronchodilators and inhaled corticosteroids were regularly used by 82 (84.4%) and 44 (45.3%) patients, respectively, while 13 patients used domiciliary oxygen. Among the patients, 40.2% showed evidence of right heart failure and 51.5% presented with radiological features of chest infection. Type 1 exacerbations were diagnosed in 43% of patients. Thirty-nine per cent of all patients had been hospitalized with AECOPD in the past, with 17% requiring mechanical ventilation. Forty-six patients (56.9%) required mechanical ventilation for a median of 5 days (range 1 to 34) during their current hospital stay. The median duration of hospital stay was 13 days (range 1 to 77).

At the time of reassessment before planned discharge, dyspnoea, total leucocyte counts, erythrocyte sedimentation rate, partial pressure of arterial carbon dioxide, haemoglobin, urea, creatinine, potassium and serum glutamic pyruvic transaminase levels, arterial pH and serum albumin concentrations had all returned to normal (Table 1). Serum CRP and fibrinogen levels declined significantly compared with baseline levels, but remained elevated. The correlations between the differences in baseline and pre-discharge CRP, IL-6 and fibrinogen levels and changes in other clinical and laboratory parameters are shown in Table 2. There were no significant differences in the levels of these markers between patients with mild/moderate or severe exacerbations, or between patients who did or did not require mechanical ventilation. Several baseline parameters, including IL-6 and fibrinogen levels, significantly predicted a prolonged duration of mechanical ventilation (Table 3). Similarly, IL-6 was the only inflammatory marker, apart from the presence of chest infection, requirement for mechanical ventilation and blood pressure that significantly predicted the total duration of hospital stay.

Table 1.  Baseline and pre-discharge clinical characteristics of the patients
ParameterAt admission (n = 97)At discharge (n = 97) P value
  1. Values are expressed as median (min, max). Wilcoxon sign rank test was used to compare change in medians.

  2. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Hb, haemoglobin; IL-6, interleukin-6; MRC, Medical Research Council; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen; SGPT, serum glutamic pyruvic transaminase; TLC, total leucocyte count.

Respiratory rate, per min24.1 (5.47)14.60 (1.65)0.001
Dyspnoea, MRC score3.69 (1.19)1.60 (0.57)0.001
pH7.28 (0.12)7.38 (0.08)0.001
PaCO2, mm Hg71.58 (21.97)50.11 (10.70)0.001
PaO2, mm Hg80.09 (40.56)86.82 (18.57)0.13
Hb, gm%13.41 (2.67)12.59 (1.83)0.001
TLC, ×109/L14.95 (5.73)9.63 (3.94)0.001
ESR, mm37.01 (13.28)24.60 (10.72)0.001
Urea, mg%46 (4.6–196)31 (11–80)0.001
Creatinine, mg%1.25 (0.81)0.84 (0.23)0.001
Albumin, gm%3.56 (0.64)3.75 (0.72)0.007
SGPT43.5 (12–3560)32 (10–639)0.001
CRP, mg/L23.05 (2–323.5)8.9 (0.4–136.7)0.001
IL-6, pg/mL76.8 (0–200)10.6 (0–70)0.001
Fibrinogen, mg/L469 (2–655.9)188 (20–647.7)0.001
Table 2.  Correlation coefficients for the correlations between changes in inflammatory markers and other parameters
ParameterPack-years of smokingDuration of COPD, yearsDuration of ventilation, daysAPACHE II scoreΔMRC scoreΔpHΔPaO2, mm HgΔTLC, ×109/L
  • Δ denotes changes in values from baseline to pre-discharge.

  • *

    Denotes significant correlation, P < 0.05.

  • APACHE, acute physiologic assessment and chronic health evaluation; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; IL-6, interleukin-6; MRC, Medical Research Council; PaO2, partial pressure of arterial oxygen; TLC, total leucocyte count.

ΔCRP0.02−0.110.24*−0.20−0.53*0.26*0.15−0.10
ΔFibrinogen−0.25*0.34*0.37*0.34*−0.56*−0.22*0.23*0.40*
ΔIL-6−0.46*0.29*0.33*0.37*−0.11−0.170.29*0.32*
Table 3.  Correlation between various parameters and duration of mechanical ventilation
ParameterDuration of ventilation (days)
Correlation coefficient (r)β coefficientAdjusted β coefficient
  • Denotes significant correlation.

  • BP, blood pressure; CRP, C-reactive protein; DBP, diastolic blood pressure; IL-6, interleukin-6; MRC, Medical Research Council; PaCO2, partial pressure of arterial carbon dioxide; SBP, systolic blood pressure.

Age, years0.060.04
Current duration of symptoms, days0.240.180.48
Comorbidity0.411.69−5.87
Previous admissions−0.24−3.12−18.78
SBP, mm Hg−0.22−0.06−0.69
DBP, mm Hg−0.30−0.121.57
Chest infection−0.26−3.1815.55
BP support0.465.96
Fever0.202.67
Dyspnoea, MRC score0.261.35−3.00
PaCO2, mm Hg0.210.05−0.09
HCO3, mEq/L0.320.22
Haematocrit0.200.15
CRP, mg/L0.110.01
IL-6, pg/mL0.370.03
Fibrinogen, mg/L−0.280.07
R20.83
Adjusted R20.64

DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The results from this study indicated that plasma levels of inflammatory mediators are elevated in patients with AECOPD and tend to decline with clinical recovery, albeit at a slow rate. Increased systemic inflammation during AECOPD has been demonstrated previously using various markers.13–18 The formation of acute-phase reactants is strongly induced by cytokines such as IL-6. However, enhanced circulating levels of IL-6 have been reported in some, but not all studies.19–21 Increased levels of these inflammatory mediators are also associated with the production of other acute-phase reactants such as leptin and adiponectin.22

CRP was found to be a significant predictor of functional impairment, quality of life and distress due to respiratory symptoms, irrespective of age, gender and forced expiratory volume in 1 s among stable COPD patients.23 In a cohort study of 446 patients with chronic respiratory failure of whom 43% were COPD patients, serum CRP was a major determinant of hospitalization and risk of death.24 On the other hand, Gompertz et al.2 failed to show a significant association between serum CRP levels and the frequency of exacerbations in 40 COPD patients. In another recent study, 36 biomarkers were assessed in 90 paired baseline and exacerbation plasma samples from patients with COPD.13 Plasma CRP levels, in conjunction with a major exacerbation symptom, were found to be useful for confirming COPD exacerbations, as well as predicting the response to antibiotics.25 However, none of the systemic biomarkers were helpful in predicting the severity of exacerbations.

The temporal profile of inflammatory mediators during an acute episode has been less well studied. Although there is sufficient evidence in favour of increased inflammation as a risk factor for future exacerbations, the relationship of inflammation to indices of mortality and morbidity is less clear. Systemic inflammation increases the risk of all-cause mortality among COPD patients, mainly due to cardiovascular events and cancer.26 However, the role of inflammatory mediators in hospital-related morbidity is not well defined. The present data showed that changes in CRP levels correlated well with the duration of mechanical ventilation and severity of dyspnoea on the Medical Research Council scale. Changes in fibrinogen levels correlated well with several clinical and laboratory parameters, notably the acute physiologic assessment and chronic health evaluation II score, pack-years of smoking and duration of disease, as shown in Table 2. Therefore, fibrinogen appeared to be a more reliable and broader marker for assessing changes in the inflammatory response and their correlation with other parameters during recovery from AECOPD, as compared with CRP and IL-6. There was a significant association between pack-years of smoking and some biomarkers (Table 2); therefore, partial correlation coefficients were computed to assess the magnitude of the correlations between differences in these biomarkers and each of the other parameters, after adjustment for pack-years of smoking. This adjustment was performed to control for the possible effect of non-smoking on hospitalized patients during the study period.

Previously, Perera et al.16 attempted to examine the relationships among recovery from exacerbations, recurrent exacerbations and inflammation. In that study, inflammatory changes during COPD exacerbations were related to clinical non-recovery and recurrent exacerbations within 50 days. Non-recovery from symptoms of COPD exacerbation is associated with persistently heightened systemic inflammation. In another study involving 20 patients hospitalized with AECOPD, significant changes in serum IL-6, IL-8 and tumour necrosis factor-α levels were found to correlate with symptoms and lung function.17 In contrast, a recent study failed to find any association between plasma CRP levels and in-hospital outcome of AECOPD, although CRP levels showed a direct correlation with severity of exacerbation according to Anthonisen's classification.27 Similarly, another recent study of 20 patients did not show serum IL-6 to be a useful indicator for monitoring the course of COPD exacerbations, although IL-6 levels were increased compared with a control group.14 More recently, sequential evaluation of IL-6, CRP and tumour necrosis factor-α in 30 patients with AECOPD showed that CRP and IL-6 levels returned to normal by day 3, whereas fibrinogen levels returned to normal after 5–6 weeks. However, none of the measured inflammatory markers correlated with functional or biochemical changes during recovery.15 In another study of 21 patients with AECOPD, serial measurements of plasma IL-6 showed that there was a rapid decline, with baseline values being reached when the patient was clinically stable.28

In the present study, the duration of mechanical ventilation depended significantly on baseline IL-6 and fibrinogen levels, among several other clinical and biochemical variables that were measured, as shown in Table 3. The total duration of hospital stay depended on the presence of chest infection, requirement for mechanical ventilation, blood pressure and baseline IL-6 levels. The combination of these clinical variables and partial pressure of arterial oxygen explained 83% of the variability in predicting the duration of mechanical ventilation. Interestingly, baseline erythrocyte sedimentation rate, which is often used to monitor the regression of inflammation, did not appear to correlate with the duration of ventilation or hospital stay. Furthermore, during the hospital stay, a significant drop in haemoglobin concentrations was observed, although serum albumin concentrations increased. This may be due to irregular dietary intake during the hospital stay together with a hypermetabolic state as a result of acute illness. The improvements in dyspnoea, leucocyte counts, erythrocyte sedimentation rate and arterial blood gas values clearly signified recovery from acute infection and respiratory compromise (Table 1). Although CRP, IL-6 and fibrinogen levels declined significantly with clinical recovery, none of these values returned to normal until the patient was discharged. This may imply that the inflammatory response lags behind clinical and biochemical improvement following AECOPD. This may further justify the use of oral/inhaled corticosteroids in these patients until the systemic inflammatory process subsides.

In conclusion, AECOPD are associated with an increased systemic inflammatory response. This response declines with recovery but lags behind clinical and biochemical indices of improvement. The changes in these markers of inflammation correlated with several patient- and disease-related parameters, and hence, may be used as additional tools to monitor the clinical course in this setting.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES