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(Chest. 2007;131:37-43.)
© 2007 American College of Chest Physicians

Systemic Cytokines, Clinical and Physiological Changes in Patients Hospitalized for Exacerbation of COPD*

Victor M. Pinto-Plata, MD, FCCP; Guy Livnat, MD; Mirle Girish, MD, FCCP; Howard Cabral, PhD; Phil Masdin, PhD; Paul Linacre, BSC (Hons); Rick Dew, PhD; Lawrence Kenney, MD, FCCP and Bartolome R. Celli, MD, FCCP

* From the Division of Pulmonary and Critical Care Medicine (Drs. Pinto-Plata, Livnat, Girish, Dew, Kenney, and Celli), St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA; Boston University School of Public Health (Dr. Cabral), Boston, MA; and Respiratory and Human Biomarkers Centers (Dr. Masdin and Mr. Linacre), GlaxoSmithKline, Stevenage-Ware, UK.

Correspondence to: Bartolome R. Celli, MD, FCCP, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135; e-mail: bcelli{at}copdnet.org

Abstract

Background: Systemic inflammation in patients with COPD may worsen during exacerbations, but there is limited information relating levels of systemic inflammatory markers with symptoms and physiologic changes during an exacerbation

Methods: We measured dyspnea using the visual analog scale, pulmonary function tests, hemograms, and plasma levels for interleukin (IL)-6, IL-8, leukotriene B4 (LTB4), tumor necrosis factor-{alpha}, and secretory leukocyte protease inhibitor (SLPI) in 20 patients on admission to a hospital for exacerbation of COPD (ECOPD), 48 h later (interim), and 8 weeks after hospital discharge (recovery).

Results: Dyspnea was present in all patients. Inspiratory capacity improved faster than FEV1. Compared to recovery, there was a significant increase in the mean (± SD) hospital admission plasma levels of IL-6 (6.38 ± 0.72 to 2.80 ± 0.79 pg/mL; p = 0.0001), IL-8 (8.18 ± 0.85 to 3.72 ± 0.85 pg/mL; p = 0.002), and LTB4 (8,675 ± 1,652 to 2,534 ± 1,813 pg/mL; p = 0.003), and the percentages of segmented neutrophils (79 to 69%; p < 0.02) and band forms (7.3 to 1.0%; p < 0.01) in peripheral blood, with no changes in TNF-{alpha} and SLPI. There were significant correlations between changes in IL-6 (r = 0.61; p = 0.01) and IL-8 (r = 0.56; p = 0.04) with changes in dyspnea and levels of IL-6 (r = –0.51; p = 0.04) and TNF-{alpha} (r = –0.71; p < 0.02) with changes in FEV1.

Conclusions: Hospitalized patients with ECOPDs experience significant changes in systemic cytokine levels that correlate with symptoms and lung function. An ECOPD represents not only a worsening of airflow obstruction but also increased systemic demand in a host with limited ventilatory reserve.

Key Words: chronic obstructive lung disease • cytokines • dyspnea • exacerbation

COPD is characterized by an abnormal inflammatory response of the lungs to noxious particles.1 The presence of systemic inflammation has been suggested by studies234567 showing increased oxidative stress, the activation of circulating neutrophils and lymphocytes, increased plasma levels of tumor necrosis factor (TNF)-{alpha} and its receptors, interleukin (IL)-6, IL-8, endothelin-1, and C-reactive protein (CRP), and the expression of adhesion molecules and G proteins in circulating neutrophils.

During an exacerbation of COPD (ECOPD), there are changes in the sputum levels of IL-6, IL-8, TNF-{alpha}, myeloperoxidase, neutrophil elastase, and leukotriene B4 (LTB4) suggesting an inflammatory burst,8910 which also has been detected in exhaled breath condensate.11 There is less information regarding the systemic inflammation response during an ECOPD,571213 including changes in peripheral blood WBC count and plasma cytokine levels. Further, the respiratory, metabolic, and physiologic events that take place during an ECOPD are only beginning to be characterized,1415 and their correlation with systemic cytokine changes has not been studied.

We hypothesized that patients with COPD have limited ventilatory reserve and that the systemic inflammatory response could lead to increased ventilatory demand that might not be adequately met, thus generating the characteristic severe dyspnea experienced in exacerbations. The systemic involvement could be captured by measuring peripheral WBC and plasma cytokine levels. To test this hypothesis, we prospectively studied patients who had been hospitalized for ECOPDs.

Methods and Materials

We studied 20 consecutive patients who had been admitted with an ECOPD to Caritas St. Elizabeth’s Hospital. The protocol approved by the institutional review board of the hospital was signed by all participants. The diagnosis of ECOPD was confirmed if patients had two or more of the following three symptoms of exacerbations16: worsened dyspnea; worsened sputum volume and/or change in its color; and new or worsening cough. All patients had received a diagnosis of COPD based on smoking history (> 20 pack-years), FEV1/FVC ratio of < 0.7, and FEV1 of < 70% predicted. Only patients requiring admission to the hospital by the criteria of the American Thoracic Society/European Respiratory Society17 were included in the study (level II, hospitalization in a medical ward but not in the ICU). Exclusion criteria were as follows: current smokers; infiltrate seen on radiograph; infection from any other organ; heart failure; myocardial infarction; pulmonary embolism; asthma; or the need for ventilatory support.17 The treatment included therapy with inhaled ß-agonist and anti-cholinergic agents, IV methylprednisolone (60 mg/8 to 12 h for 2 to 3 days), followed by oral prednisone over 2 weeks and IV antibiotics for 3 days followed by a 10-day oral course.

Clinical Variables
We recorded the presence of comorbid conditions, medical history, baseline lung function, and medications. Patients were encouraged to expectorate, and the sputum collected was processed for Gram stain and culture. Dyspnea was quantified using the visual analog scale (VAS), which consisted of a 10-cm line on which 0 represents "no breathlessness" and 10 represents "extremely short of breath." We also recorded symptoms of sore throat, malaise, fever, and wheezes, pulse, respiratory rate, temperature, weight, arterial blood gas levels, oxygen saturation, use of oxygen, accessory muscle, pulmonary sounds, presence of a left ventricular gallop, increased jugular vein distention, and extremity edema. Routine laboratory tests included a CBC count with a differential count. We measured FEV1, FVC, and inspiratory capacity (IC) with a spirometer (Vmax 29; SensorMedics; Yorba Linda, CA) according to American Thoracic Society recommendations.18 The IC was measured after the patient reached a stable baseline (ie, at least three breaths reaching a stable end-expiratory lung volume). The best value from three attempts was used.

Cytokine Analysis
Blood samples were drawn in a heparanized tube, kept on ice, and centrifuged at 2,000 revolutions per minute for 10 min within 1 h of being drawn. The plasma was separated in aliquots and frozen at –80°C. The analysis was blindly conducted in Ware, UK, by investigators who had no information related to the patients. The cytokines were selected based on studies reporting their presence in BAL fluid or sputum in patients with ECOPDs. Concentrations of IL-6 and IL-8 were analyzed using ultrasensitive enzyme-linked immunosorbent assays (Biosource; Nivelles, Belgium). Levels of TNF-{alpha} and secretory leukocyte protease inhibitor (SLPI) were measured using available enzyme-linked immunosorbent assays (R&D Systems; Minneapolis, MN). LTB4 was measured using a competitive enzyme immunoassay (R&D Systems). These measurements were performed using the instructions from the manufacturers. The lower limits of quantification for the different assays are as follow: IL-6, 0.16 pg/mL; IL-8, 0.39 pg/mL; TNF-{alpha}, 1 pg/mL; LTB4, 93.8 pg/mL; and SLPI, 1.25 ng/mL. All tests including cytokine analyses were performed at baseline (before treatment), repeated at 48 h (recovery), and 8 weeks after hospital discharge.

Statistical Analysis
All numerical values are expressed as the mean ± SD. The significance of changes over time was determined using one-way analysis of variance. A paired t test was used to detect differences between individual time points. The amount of plasma collected was insufficient to measure all the cytokines levels at all time points. The cytokines to be measured at each time point were randomly chosen by the laboratory in the United Kingdom. To correct for the difference in sample numbers, the significance of the changes in cytokines over time was determined using a mixed linear model (ie, regression models for longitudinal data with unequal numbers of observations per subject), using the time of the evaluation (ie, hospital admission, interim, and recovery) as a categoric variable. A Wilcoxon test was used to evaluate differences in categoric values. The interrelationships among symptoms, physiologic variables, and level of cytokines were determined using Pearson correlations (for normally distributed data) and Spearman correlation (for nonnormally distributed data [cytokines]). Comparisons for clinical and physiologic variables were determined using absolute values of the changes, and for cytokines and physiologic parameters the changes occurring between hospital admission and recovery were first expressed as percentage change; this value used to estimate the correlation. A p value of < 0.05 was deemed to be significant.

Results

The characteristics of the patients are shown in Table 1 . The patients were elderly ex-smokers with preexacerbation mean FEV1 values of 41 ± 13% predicted. On hospital admission, the majority of patients (67%) required oxygen therapy and had increased WBC counts with predominant segmented neutrophils and increased band forms.


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  		Table 1. Anthropometrics, Smoking History, Comorbidity Index,33 Lung Function, and Arterial Blood Gas Levels in Patients With ECOPDs

 
Clinical and Physiologic Changes
Dyspnea was seen in 100% of patients, and cough and wheeze were seen in 68% of patients, followed by the presence or change in sputum volume (55%) and color in 45% of patients. Fever (ie, temperature, 38.1°C) [45% of patients] and sore throat (35% of patients) were less prevalent.

Figure 1 shows that the values for respiratory rate, pulse, and the intensity of dyspnea were markedly increased in all patients at the moment of hospital admission with a significant reduction in measurements at all intervals thereafter. There was a significant reduction in temperature, but it was of little clinical relevance (reduction, –0.7°C [data not shown]).


Figure 1
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  		Figure 1. The changes in respiratory rate, pulse, and dyspnea occurred very rapidly from the moment of hospital admission and improved further by recovery time.

 
The changes in the physiologic variables are summarized in Table 2 and Figure 2 . The FEV1 and FVC improved minimally during the hospitalization. It was only after recovery that the change reached statistical significance for both measurements (FEV1 improved by190 mL [19%] at recovery). In contrast, there was a rapid improvement in IC that occurred between hospital admission and interim (230 mL [13%] at interim) and improved further after hospital discharge (610 mL [33%]). At the same time, there was also a reduction in the proportion of neutrophils (79 to 69%; p < 0.02) and band forms (7.3 to 1.0%; p < 0.01) and an increase in lymphocytes (13 to 22%; p < 0.003). There was a nonsignificant decrease in the number of WBCs (11.4 to 9.0 x 106 cells/mL; p > 0.05).


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  		Table 2. Change Over Time in Vital Signs, Dyspnea VAS, and Spirometric Measurements

 

Figure 2
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  		Figure 2. Changes in clinical and pulmonary function test parameters during hospitalization and after hospital discharge. The most rapid change occurred in IC, which had significantly improved by 48 h. The FVC and FEV1 were improved by 6 to 8 weeks after hospital discharge.

 
Cytokine Changes
The levels of IL-6, IL-8, and LTB4 were significantly different (Table 3 ). IL-6 level had the most significant mean change during hospitalization (6.38 ± 0.72 vs 2.80 ± 0.77 pg/mL, respectively; p < 0.002) and after hospital discharge compared to hospital admission. IL-8 levels also decreased during hospitalization (8.18 ± 0.85 vs 5.57 ± 0.83 pg/mL, respectively; p < 0.02) with further reduction at hospital discharge. In contrast, the level of LTB4 remained constant during the first 48 h to decrease after the recovery phase. There were no significant changes in the levels of TNF-{alpha} and SLPI.


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  		Table 3. Cytokine Level Measured on Admission to the Emergency Department Before Treatment*

 
Correlations
There were direct correlations between changes in the perception of dyspnea and changes in respiratory rate, FEV1, IL-6, and IL-8 (Table 4 ), and inverse correlations between changes in FEV1 and changes in IL-6 and TNF-{alpha}. The correlation value (r value) is higher in all of the cytokines analyses compared to the clinical findings (last four rows in Table 4). However, their p values are smaller because the number of cytokine samples was lower compared to the number of clinical observations (see "Discussion" section).


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  		Table 4. Correlation of Changes Between Hospital Admission and Recovery in Symptoms, Physiologic Measurements, and Cytokine Levels*

 
Discussion

There were several findings in this study of patients admitted with an ECOPD. First, the most prevalent symptom was measurable dyspnea. Physiologically, there was tachypnea and decreased IC. The IC improved rapidly and correlated with tachypnea. In contrast, the changes in FEV1 and FVC were more gradual, being significant only after hospital discharge. Second, the plasma levels of IL-6, IL-8, and LTB4 were increased at the moment of the initial evaluation, with rapid reductions for IL-6 and IL-8 by 48 h after the initiation of therapy, and a slower reduction for LTB4. These changes paralleled those observed in the number of segmented neutrophils and early forms in peripheral blood, and contrasted with the reduction in lymphocytes. Third, the changes in IL-6 correlated well with the changes in dyspnea and in FEV1. The change in FEV1 between hospital admission and recovery correlated with changes in IL-6 and TNF-{alpha}. Taken together, these findings suggest a measurable burst of increased systemic inflammation during ECOPD that was associated with physiologic changes that contributed to the worsened dyspnea of exacerbation.

Clinical-Physiologic Changes
There is limited information describing the clinical-physiologic changes in patients who were admitted to a hospital with an ECOPD, despite the fact that the primary "cost driver" for COPD is hospital care.19 The most likely reason is that the majority of studies have been performed in outpatients.58910142021 For the first time, we describe these changes (Table 2, Fig 1) in a group of patients who had been hospitalized for ECOPDs. Tachycardia and tachypnea were the most important signs and manifested the largest changes. All patients had scores for intense dyspnea. Indeed, the score at hospital admission was similar to that reported by patients at peak exercise.22 Cough (64%), and wheeze (64%) values were similar to those reported by Anthonisen et al16 in outpatients. VAS score for dyspnea had the largest decrease (55%) of any of the variables measured (Table 2), and its changes correlated with spirometric and cytokine measurements. These observations suggest that the accurate quantification of dyspnea is possible and could be used to easily evaluate the clinical progression of an ECOPD.

Other authors had previously described simple physiologic changes during exacerbations, including median peak flow reductions of 6.6 L/min21 and 25 L/min16during episodes. Thompson and coworkers23 showed that outpatients who had been treated with prednisone had a more rapid improvement in arterial PO2, dyspnea, FEV1, and peak expiratory flow compared to placebo. Niewoehner et al24 studied hospitalized patients and showed a mean improvement of 100 mL in FEV1 on the first day in patients receiving steroids compared to placebo. Recently, Parker et al14 and Stevenson et al15 showed a reduction in IC during ECOPDs that improved after recovery. The reductions were smaller compared to that observed in our patients (0.30 and 0.42 vs 0.61 L, respectively). However, the changes reported for FEV1 were similar to ours (0.19 and 0.2 vs 0.19 L, respectively), in a similar number of patients (20, 22, and 20 patients, respectively). Like those authors, we also noticed that the FEV1 changed little in the first 48 h. However, there was a rapid improvement in IC that occurred simultaneously with reductions in dyspnea and respiratory rate. This supports the concept that during an ECOPD dynamic hyperinflation develops akin to that seen with progressive general exercise.141522 The rapid decrease in respiratory rate and dyspnea, and the increase in IC that preceded any significant change in FEV1 suggest that the initial rapid clinical improvement was more likely due to decreased ventilatory demand, and was less likely due to simple bronchodilation. We believe that therapy, including rest, antibiotics, and corticosteroids, resulted in a rapid decrease in systemic inflammation, as measured by the reduction in proinflammatory cytokines, the decrease in respiratory rate, and the increase in IC, which improved dyspnea. We do not pretend to state that the changes in FEV1 are not important because the change in the FEV1 between hospital admission and recovery did correlate with the changes in IL-6 and TNF-{alpha} levels. However, the findings suggest that other variables such as dyspnea score, respiratory rate, and IC may help to better monitor the early changes in patients with ECOPDs.

Systemic Cytokines
There is limited information relating the clinical and physiologic changes that define ECOPDs and the changes in the systemic expressions of plasma cytokine levels. Surprisingly, we found no systematic studies describing the changes in cell count during ECOPDs. We observed an elevated WBC count before the administration of corticosteroids that dropped nonsignificantly after recovery. On the other hand, the significant increase in the proportion of neutrophils and band forms with a concomitant reduction in the proportion of lymphocytes that corrected with recovery suggests an active inflammatory process. Paradoxically, there is more information regarding systemic cytokines. Wedzicha et al25 described increased fibrinogen and IL-6 levels in plasma during ECOPD. Seemungal and collaborators26 only found a tendency toward higher plasma fibrinogen and serum IL-6 levels in patients who experienced a viral exacerbation. Roland et al5 observed that endothelin-1 plasma levels increased during exacerbations, and observed a correlation between plasma and sputum levels for endothelin-1 and IL-6. Gompertz and coworkers8 described higher CRP levels in patients with purulent bronchitis during exacerbations compared to those in patients with nonpurulent bronchitis. Likewise, Dev et al12 described an elevation of serum CRP levels in patients who had been hospitalized with ECOPDs. We observed a significant change in plasma levels of IL-6, IL-8, and LTB4 during and after exacerbations with no changes in levels of TNF-{alpha} and SLPI. Importantly, there were associations between some of these changes and changes in dyspnea and FEV1 that suggest a possible role of systemic inflammation in the genesis of the symptoms. Although we did not measure cytokines in sputum samples, previous researchers have demonstrated elevations in the levels of IL-6,10 IL-8,9 and LTB48 in the sputum of patients during ECOPDs. IL-6 is released from bronchial epithelial cells after rhinovirus infection,27 IL-8 is increased in the human bronchiolar epithelial cells of smokers with emphysema,28 but other cells such as smooth muscle, fibroblasts, and inflammatory cells are also possible sources.29 The majority of the studies of ECOPD have centered on the evaluation of the sputum, and rightly so because sputum is thought to represent the visible expression of the process causing the exacerbation. These studies have shown the role of viruses26 and bacteria30 as possible causative agents in the genesis of the episodes. They have also shown that there is an increase in sputum neutrophils,6 IL6, IL-8, TNF-{alpha},910 and other proinflammatory markers,58 all of which seem to confirm the presence of increased airway inflammation. Several studies5812202526 have extended the observations to the systemic compartment but with limited clinical information.

Correlations Between Cytokines and Clinicophysiologic Changes
Ours is the first study to include clinical and physiologic changes in ECOPDs observed during hospitalizations and their association with systemic cytokines. Based on the correlations shown in Table 4, IL-6 seems to be the best cytokine for reflecting changes in dyspnea and spirometry, of the ones we studied. It is too presumptive to state that this study provides an answer to the issue of specific cytokine pattern changes in patients with ECOPDs; however, our results indicate that the use of sensitive assays makes possible the systematic evaluation of cytokines and their relationship to the course of exacerbations. In the only study that evaluated systemic cytokine profile of patients hospitalized during an ECOPD, Noguera and coworkers31 documented an increase in IL-6 and CRP levels on hospital admission, but no change in IL-8 and undetectable levels of TNF-{alpha}. They observed no changes during therapy. Our study, however, included 20 patients, compared to 10 patients in that study, and we used an ultrasensitive cytokine analysis.

Our study had limitations. First, it only included hospitalized patients. However, this is the population that consumes the largest share of health-care resources and is at higher risk for relapse. Second, we did not include patients who needed mechanical ventilation. However, rapid, shallow breathing and severe dyspnea have been noted in several studies32 evaluating the use and effects of noninvasive mechanical ventilation. Third, our study was not specifically designed to differentiate the role of bacterial or viral infection in the pathogenesis of the exacerbation. Only 3 of the 20 patients had bacterial growth in the sputum culture even though all of the patients were encouraged to provide sputum samples for analysis. It is possible that the etiology agent (ie, virus and/or bacteria) may trigger a different level of inflammatory response, but the pathophysiologic process here described seems common to most ECOPDs. Fourth, there was not enough plasma to measure all of the cytokines in each time frame. The decision to measure a specific cytokine in a reduced aliquot was performed blindly by the researchers in the laboratory. The statistical analysis also included a mixed linear model (ie, regression models for longitudinal data with unequal numbers of observations per subjects). Therefore, it is unlikely that an error bias was introduced in the processing or analysis of the cytokine results.

This study shows that quantification of the respiratory rate and dyspnea by a VAS provides an objective description of the severity of the episode, while the measurement of inflammatory cytokines provides tools to better help in understanding the underlying pathophysiology of exacerbation. It is conceivable that the prospective evaluation of the value of cytokines such as IL-6 coupled with simultaneous measurements of VAS dyspnea, respiratory rate, and IC may better help to characterize episodes of exacerbation.

Footnotes

Abbreviations: CRP = C-reactive protein; ECOPD = exacerbation of COPD; IC = inspiratory capacity; IL = interleukin; LTB4 = leukotriene B4; SLPI = secretory leukocyte protease inhibitor; TNF = tumor necrosis factor; VAS = visual analog scale

This research was supported by an unrestricted grants from GlaxoSmithKline, Thoracic Overholt Foundation.

Drs. Masdin and Linacre are employees of GlaxoSmithKline, a pharmaceutical company with financial interest in COPD. All of the authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication March 13, 2006. Accepted for publication July 20, 2006.

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