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September - December 2005: 
Volume 18, Issue 3

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Significance of serum antioxidant status in patients with severe asthma exacerbation or community-acquired pneumonia
Abstract
Oxidative stress due to increased production of oxygen free radicals has been reported in various respiratory diseases including asthma and pneumonia. An imbalance between oxidant and antioxidant production has also been proposed in these patients. In the present study, serum total antioxidant status (TAS) was measured in patients with severe exacerbation of bronchial asthma or community-acquired pneumonia; a possible correlation between TAS and disease severity was investigated. Twenty patients (10 men, 10 women; mean age 41±20 years) admitted to hospital for severe exacerbation of asthma and thirty patients (22 men, 8 women; mean age 48±21 years) with community-acquired pneumonia were studied. Ten healthy non-smokers (44±16 years of age) were also included in the study. On days 1 and 7, serum total antioxidant status was measured using a colorimetric method in 600 nm. At the same time, clinical and laboratory severity criteria were recorded in both groups of patients. In the first measurement, TAS values were found statistically significantly lower in both asthma and pneumonia patients compared to normal subjects (0.98±0.08 vs 1.19±0.09 mmol/L, p<0.001; and 0.84±0.13 vs 1.19±0.09 mmol/L, p<0.001, respectively). TAS values obtained on day 1 were also lower compared to the respective values on day 7 in both groups of patients (0.98±0.08 vs 1.12±0.17 mmol/L, p<0.001; 0.84±0.13 vs 1.00±0.17 mmol/L, p=0.0001, respectively). In asthmatic patients, TAS changes correlated with FEV1 changes (r=0.58, p=0.007). In pneumonia patients, TAS changes were associated with factors predisposing to pneumonia (p>0.001), complications (p=0.005), and pneumonia caused by Gram(-) bacteria (p=0.008). Additionally, TAS changes correlated with white blood count (r=0.39, p=0.03), especially polymorphonuclear cell count (r=0.36, p=0.05). Finally, the comparison between TAS values in asthma and pneumonia showed statistically significantly lower values in pneumonia in both measurements (0.84±0.13 vs 0.98±0.08 mmol/L, p<0.001; 1.00±0.17 vs 1.12±0.17 mmol/L, p<0.001, respectively). We concluded that serum total antioxidant status in patients with severe exacerbation of bronchial asthma or community-acquired pneumonia is relatively low at the onset of the disease. In the course of the disease, an increase in total antioxidant status is consistent with clinical and laboratory improvement. Total antioxidant status changes are associated with respective changes in parameters related to disease severity in both asthma and pneumonia patients. Pneumon 2005, 18(3):315-324.
Full text

INTRODUCTION

Oxygen free radicals, antioxidants and oxidative stress in general have drawn much attention in the last few years, since oxidative stress appears to be implicated in a growing number of diseases. Oxygen free radicals or reactive oxygen species (ROS) are byproducts of normal aerobic metabolism and are eliminated through complex antioxidative pathways that involve enzymes such as superoxide dismutase, catalase, glutathione peroxidase, as well as other compounds including vitamins C and E, β-carotene, transferrin, ceruloplasmin, lactoferrin, uric acid etc.


An oxidant-antioxidant imbalance has been reported in a large number of lung diseases, including acute respiratory distress syndrome, bronchopulmonary dysplasia, emphysema, pneumonoconiosis, hyperacute bleomycin toxicity, cystic fibrosis, bronchial asthma and pneumonia.2,3 In asthma, in particular, many studies have reported abnormal levels of specific antioxidants. Furthermore, it has been suggested that such abnormalities may be associated with increased asthma incidence, as well as with the pathogenesis of the disease.4-6 Antioxidant imbalance has also been reported in pneumonia patients; nevertheless, the number of relevant studies is limited.7,8 However, no study in the international literature has examined until now total antioxidant status in severe asthma exacerbation or pneumonia.


In last years, laboratory methods for the measurement of total antioxidant capacity or status in biological fluids such as blood serum or plasma have been developed. Hence, apart from the advantage of determining the total antioxidant capacity of a certain sample, the difficulties associated with the development and performance of separate assays for the individual components of a complex antioxidant pathway are eliminated.9,10

 

Since both asthma and pneumonia are conditions characterized by oxidative stress, we assumed that this would be reflected on the total antioxidant status of blood serum. To examine this assumption, we enrolled patients admitted to hospital for severe asthma exacerbation or community-acquired pneumonia. Total antioxidant status (TAS) of blood serum during hospital stay was measured; possible associations with laboratory and clinical findings related to the severity of these conditions were investigated.




PATIENTS - METHODS

The characteristics of patients with asthma and pneumonia are shown in Tables 1 and 2, respectively. In total, 50 patients were enrolled; 20 with severe asthma exacerbation (10 men, 10 women; mean age 41±20 years) and 30 with community-acquired pneumonia (22 men, 8 woen; mean age 48±21 years). Ten healthy non-smokers (8 men, 2 women; mean age 44±16 years) were also included in the study as controls.

Άσθμα
   Όλοι
(n=20)

Μη καπνιστές
(n=10)

 
Καπνιστές
(n=10)

 
 Ηλικία
(χρόνια)
FEV1 (Lt)
Εισαγωγής
FEV1 (Lt)
Εξόδου
PaO2 (mmHg)
εισαγωγής
PaO2 (mmHg)
εξόδου
Κάπνισμα
(πακέτα-έτη)
 42±21
(19-80)
1,47±0,72
0,5-3,1)
2,6±1,12
0,9-4,5)
63±11
(47-80)
80±23
(70-100)
22±21
(2-60)
37±18
(19-66)
1,44±0,59
(0,7-2,7)
2,79±1,11
(1,10-3,95)
61±9
(47-77)
80±29
(70-81)
22±21
(2-60)
 
47±22
(21-80)
1,51±0,85
(0,5-3,1)
2,37±1,15
(0,9-4,5)
64±12
(47-80)
80±14
(70-100)
 
Τα δεδομένα εκφράζονται ως μέσες τιμές με τη διακύμανση σε παρένθεση    
       




No one of the study subjects had received treatment with oral steroids at least 1 month prior to their inclusion in the study; patients treated with other agents with known antioxidant effects, including trimetazidine, non-steroidal anti-inflammatory agents, acetylsalicylic acid or nimesulide, were also excluded. Patients were not included in the study if disease duration prior to admission was longer than four days or if their hospital stay was shorter than 7 days.

Πίνακας 2. Χαρακτηριστικά ασθενών με πνευμονία.
    Πνευμονία
   Όλοι
(n=30)
 Μη καπνιστές
(n=11)
 καπνιστές
(n=19)
Ηλικία
(χρόνια)
PaO2 (mmHg
εισαγωγής
PaO2 (mmHg
εξόδου
Βαθμολογία
βαρύτητας εισόδου
Βαθμολογία
βαρύτητας εξόδου
Αριθμός λευκών
αιμοσφαιρίων εισόδου
Αριθμός λευκών
αιμοσφαιρίων εξόδου
Κάπνισμα
(πακέτα-έτη)
 
48±21
(20-87)
73±14
(37-98)
78±14
(45-98)
71±35
(30-158)
56±31
(20-113)
13576±5992
(5000-28000)
8907±3191
(4840-20000)
21±20
(2-60)

 


55±20
(21-80)
66±13
(37-85)
75±14
(45-95)
83±40
(31-158)
64±31
(21-113)
15490±695
(8800-2800)
8349±2130
(4840-11770)
21±20
(2-60)



 
43±22
(20-87)
77±14
(51-98)
80±14
(53-98)
64±31
(30-117)
50±31
(20-107)
2468±5242
(5000-22600)
9230±3685
(5060-20000)
21±20
(2-60)




Venous sampling for complete blood count and biochemistry analysis was performed on day 1 (admission) and day 7. An aliquot of venous blood (5 ml) was used for the measurement of total antioxidant status (TAS) of serum on day 1 (TAS1) and day 7 (TAS7) of the hospital stay.



Patients with asthma

As regards asthma patients, a comprehensive history was taken on admission; in particular, smoking habit, history of atopy and prior drug treatment were recorded. Clinical and laboratory criteria of asthma severity according to the recent international guidelines were recorded on day 1 and day 7,11


Patients with community-acquired pneumonia

On admission of a patient with community-acquired pneumonia, a detailed medical history was obtained, with special reference to smoking habit, factors that predispose to pneumonia and previous treatment. Clinical and laboratory severity criteria present on day 1 and day 7 were recorded according to the criteria formulated by the American Thoracic Society;12 in addition, a severity score was calculated according to the rules specified by Fine et al.13 A posteroanterior and a lateral chest radiograph were obtained in order to determine the type and extent of parenchymal involvement (unilateral, bilateral, lobar), as well as to detect a pleural effusion that might have complicated pneumonia. The investigation of the etiological agent included sputum Gram stain and culture for common pathogens (aerobic, anaerobic), blood cultures, pleural fluid Gram stain and culture for aerobic and anaerobic organisms (if the amount of the effusion allowed thoracentesis).



Venous sampling and total antioxidant status  measurement
On days 1 and 7, 5 ml of venous blood were obtained at approximately the same time in the morning. Within 1 hour from venopuncture, the samples had been centrifuged for 10 minutes at 3,000 rpm; serum was separated and stored in deep freeze at -70 oC, until the time of measurement. Study samples were collected in a 6-month period and measurements were performed on all samples simultaneously. The assay kit used for the measurement of serum total antioxidant status was provided by Randox Ltd, Crumlin, Co Antrim, UK; it is a colorimetric assay at 600 nm, appropriate for serum samples.14

 


Statistical analysis

The statistical software SPSS (version 11.5) was used for the statistical analyses. The results of total antioxidant status (TAS) measurements were expressed as mean±standard deviation. A paired t-test was used in both patient groups for the comparison of TAS values on days 1 and 7. Unpaired t-test was used for the comparison between TAS values on days 1 and 7 and TAS values in healthy controls. A Pearson bivariate correlation analysis was performed to examine the relationship between the change in TAS (ΔTAS = TAS2-TAS1) and the change in FEV1 (forced expiratory volume in 1 sec in spirometry). A multivariate analysis was also performed, entering TAS1, TAS2 and ΔTAS as dependent variables and smoking habit, exogenous asthma and inhaled steroid treatment as constants. In patients with pneumonia, a Pearson correlation analysis was performed between ΔTAS and white blood cell count and polymorphonuclear cell count (on admission). In multivariate analysis, TAS1, TAS2 and ΔTAS were once again the dependent variables and smoking habit, radiographic findings, complications, predisposing factors and Gram stain were constants. In all tests, null hypothesis was rejected if calculated probability was less than 0.05 (p<0.05).

 

 

RESULTS

 

Patients with asthma

Ten of the 20 patients with asthma were smokers; fifteen had exogenous and 5 had intrinsic asthma, as indicated by positive history of relevant symptoms and positive skin tests for common allergens. Fifteen patients were taking inhaled steroids prior to disease exacerbation. No asthma patient required admission to the Intensive Care Unit (ICU).

 

 

Patients with community-acquired pneumonia

Nineteen patients with pneumonia were smokers; eleven had factors predisposing to pneumonia (heart failure: n=5; chronic obstructive pulmonary disease: n=4; immunosuppression: n=2); and twenty patients had leukocytosis >20,000/mL in peripheral blood on admission. Fourteen patients developed complications (parapneumonic effusion: n=10, empyema: n=3, and arthritis: n=1). Two of the patients with empyema were managed with closed thoracic drainage and one was admitted to the thoracic surgery department for open drainage through thoracotomy. No study patient required ICU admission. Regarding radiographic findings, five patients showed bilateral infiltrates on chest radiograph and eleven had lobar consolidation.

 

The etiologic agent was detected in twelve cases (40%), primarily from sputum Gram stain, positive blood culture and positive pleural fluid culture. The most common pathogens were: Streptococcus pneumoniae (n=5), Haemophilus influenzae (n=3), Branhamella catarhallis (n=2), Klebsiella pneumoniae (n=1) and Acinetobacter (n=1).

 

 

Total antioxidant status

Figure 1A. TAS values on admission [(TAS1) •] and on day
7 of hospitalization [(TAS2) ] in patients with asthma and in
subgroups according to smoking habit.
 
 
Figure 1B. TAS values on admission [(TAS1) •] and on day
7 of hospitalization [(TAS2) ] in patients with pneumonia and in
subgroups according to smoking habit.

Statistically significantly lower value of serum total antioxidant status on admission (TAS1) was found in both asthma and pneumonia patients as compared to healthy controls (0.98±0.08 vs 1.19±0.09 mmol/L, p<0.001; and 0.84±0.14 vs 1.19±0.09 mmol/L, p<0.001, respectively). TAS1 was also significantly lower than TAS2, i.e. the result of the TAS measurement on day 7, in both patient groups (0.98±0.08 vs 1.12±0.17 mmol/L, p<0.001; and 0.84±0.13 vs 1.00±0.17 mmol/L, p<0.001, respectively) (Figures 1A and 1B). TAS2 values in asthma patients were closer to normal range (1.12±0.01 vs 1.19±0.09 mmol/L, p=0.26) in contrast to the respective values in patients with pneumonia, which remained well below normal levels (1.00±0.17 vs 1.19±0.09 mmol/L, p=0.005). Dividing asthma patients in two groups according to their smoking habit, i.e. non-smokers and smokers, we were able to find statistical differences in TAS1 and TAS2 between the two groups (0.98±0.096 vs 1.16±0.21 mmol/L, p=0.006; and 0.98±0.08 vs 1.07±0.12 mmol/L, respectively) (Figure 1A). Similar differences were documented in patients with pneumonia (0.86±0.13 vs 1.00±0.19 mmol/L, p=0.003; and 0.83±0.14 vs 1.00±0.17 mmol/L, p<0.001) respectively) (Figure 1B). The comparison of TAS1 and TAS2 values in patients with asthma and patients with pneumonia showed lower TAS values in pneumonia in both measurements (0.84±0.13 vs 0.98±0.08 mmol/L, p<0.001; and 1.00±0.17 vs 1.12±0.17 mmol/L, p<0.001, on day 1 and day 7, respectively). Nevertheless, there was no relationship between TAS1, TAS2, or ΔTAS and smoking, exogenous or intrinsic asthma, or treatment with inhaled steroids prior to study entry. In patients with pneumonia, there was no relationship between TAS1, TAS2, or ΔTAS and smoking, or lobar and bilateral lung involvement in chest radiograph. However, there was a significant association between ΔTAS and factors predisposing to pneumonia (p<0.0001), presence of complications on admission (p=0.005) and pneumonia caused by Gram (-) bacteria (p<0.008) (Table 3). In addition, ΔTAS correlated with white blood cell count on admission (r=0.39; p=0.03); in particular, ΔTAS correlated with polymorphonuclear cell count (r=0.36; p=0.05) (Figure 3).

 

Figure 2. Correlation of change in TAS (ÄTAS) with change in FEV1
(ÄFEV1) in patients with asthma.

 

 

 

Table 3. Multivariate analysis of characteristics of patients with pneumonia and TAS values.

p = probability
Smoking habit
Lobar consolidation
Bilateral involvement
Predisposing factors
Gram (-) pathogen
Complications

0,58
0,61
0,81
0,47

0,99
0,73

0,87
0,98
0,46
0,008*

0,21
0,28

0,17
0,13
0,28
0,000*

0,008*
0,005*

*Statistically significant differences
     
       

 

 

Figure 3. Correlation of change in TAS (ΔTAS) with white blood cell
or polymorphonuclear cell count in peripheral blood on admission in
patients with pneumonia.

 

DISCUSSION

This study showed that total antioxidant status (TAS) in the blood serum of patients with severe asthma exacerbation or community-acquired pneumonia is decreased at disease onset. In both conditions, TAS increases within 7 days along with the observed improvement of key clinical and laboratory abnormalities. Decreased TAS is indicative of an oxidant-antioxidant imbalance, apparently due to increased oxidative stress.

 

The decrease in TAS found in asthmatic patients is in concordance with the findings of Rahman et al,15 who reported decreased serum total antioxidant capacity in 11 patients with asthma exacerbation. Studies of peripheral blood have shown decreased serum vitamin C and albumin levels; in contrast, ceruloplasmin levels were increased.16However, studies in pediatric populations have failed to show significant changes in the concentrations of vitamin C, retinol, a-tocoferol, uric acid, β-carotene or lycopene, probably because both relevant studies included patients with stable, controlled asthma. Reduced serum selenium concentration have also been reported; selenium is an essential component of glutathione peroxidase.19,20 On the other hand, however, increased serum selenium levels have been found in patients receiving corticosteroid treatment, which probably reflect the mineralocorticoid effect of the treatment, resulting in reduced renal excretion of selenium.21
Nevertheless, several studies of antioxidants in asthma have produced contradictory results; this situation has been attributed to the inclusion of subjects with varying disease severity; the examination of antioxidants of different nature; and possible differences in the role of intracellular and extracellular antioxidant systems. Hence, in patients with mild asthma, no difference in catalase or glutathione peroxidase activity has been demonstrated;22nevertheless, overexpression of glutathione peroxidase was found in eosinophils.23

 

With reference to existing evidence, the present study features two particular aspects of the topic of antioxidant defense. Firstly, we focused on severe asthma exacerbation requiring hospital admission; and, secondly, we measured serum total antioxidant status, thus avoiding measurements of individual components of the complex antioxidant defense system on one hand, and obtaining a global picture of the antioxidant capacity in the specific biological fluid on the other.

 

Interestingly, the change in FEV1 (ΔFEV1) from day 1 to day 7 correlates with the change in TAS (ΔTAS). The effects of oxygen free radicals include constriction of bronchial smooth muscle, increased mucus production and increased small vessel permeability which in turn results in edema formation.3 The simultaneous improvement in spirometry parameters as well as in total antioxidant capacity suggests that TAS is directly related to asthma severity; improved antioxidant capacity apparently has an impact on one or more pathogenetic mechanisms of airway obstruction through elimination of free radicals and inhibition of at least some of their unfavorable effects on the airways. The described findings are consistent with those of previous studies reporting an inverse relationship of peroxide dismutase activity or peroxide anion production by neutrophils with FEV1.24,25

 

The present study showed no difference in TAS between patients with exogenous or intrinsic asthma, or between those receiving treatment with inhaled steroids and those who were not receiving such treatment. The lack of an inhaled steroid effect has also been reported by Rahman et al,15 who found that inhaled steroids have no effect on plasma total antioxidant capacity inpatients with asthma. Treatment with oral prednisolone 15 mg increases selenium levels in plasma; however, inhaled beclomethasone does not seem to influence plasma antioxidant status, although it actually induces red blood cell enzymes with antioxidative activity.21,26 Hence, it appears that low dose and local action account for the lack of effect of inhaled steroids on serum total antioxidant status in contrast with the effects of systemic corticosteroids which are known to suppress inflammatory cells including eosinophils and neutrophils. In the present study, all patients received systemic corticosteroids during their hospital stay, which most probably contributed to both disease and TAS improvement. Nevertheless, the decision not to include corticosteroids in the treatment of the study subjects would be against medical ethics.

 

Despite the lack of evidence relating to the anticipated change in antioxidant capacity in the course of treatment in patients with pneumonia, the period of 7 days was chosen in the present study based on clinical experience; most patients show clinical and laboratory improvement within 7 days. To date, studies of antioxidant capacity in such patients are limited and results inconsistent. To mention but a few, Umeki et al report reduced peroxide dismutase activity,7while Duflo et al found no significant difference.27Still, increased levels of vitamin E and glutathione peroxidase activity in plasma have been demonstrated.228On the contrary, vitamin C levels in plasma and white blood cells were decreased in elderly patients with pneumonia; this was also the case for vitamin A levels in plasma in children.29,30

 

Although there was no relationship between TAS1, TAS2 and ΔTAS and the development of either lobar or bilateral parenchymal disease, ΔTAS correlated with the presence of factors predisposing to pneumonia. This is a rather expected finding since conditions such as COPD and heart failure, which are associated with a relatively high risk of pneumonia, are accompanied by oxidative stress; consequently, such patients present an additional oxidative load that apparently requires a greater increase in antioxidant capacity.
Similar findings were demonstrated in patients presenting complications on admission or patients with pneumonia caused by Gram(-) organisms. For the latter, in particular, existing evidence suggests that cell wall components of Gram(-) organisms, especially lipopolysaccharides (LPS), induce changes in the expression of specific enzymes, thus promoting both the inflammatory response and oxygen free radical production with a parallel change in the activity of antioxidant enzymes, including peroxide dismutase, glutathione peroxidase and catalase.31

 

White blood cell count, as well as polymorphonuclear cell count were also shown to correlate with changes in total antioxidant status. It has been established that polymorphonuclear neutrophils are important in defense against disease, especially against pneumonia,32through the release of various enzymes and, primarily, the production of oxygen free radicals with a process referred to as "respiratory burst",33,34thus destroying potential pathogens. This may in part explain the finding that the greater the polymorphonuclear cell count found in the present study, the greater the increase in antioxidant activity, probably as a response to the increased release of oxygen free radicals.
An additional interesting finding of the study was that in both asthma and pneumonia, serum total antioxidant status was not related to smoking. At first glance, this may be in conflict with the knowledge that smoking causes oxidative stress and influences antioxidant systems in blood.35 However, similar findings have also been reported in other studies; a plausible explanation might be that smoking primarily activates neutrophils in the airways and lung parenchyma; such an activation may not be reflected to measurements of oxidant or antioxidant activity in peripheral blood or serum samples.36

 

Comparisons of respective TAS values between the two conditions studied showed that pneumonia was associated with lower TAS values compared to asthma both on day 1 and day 7. Certainly, these conditions have completely different pathophysiology basis and predisposing factors. However, since both disease duration and change in total antioxidant status are similar in the two patient groups, we can by exclusion suggest that the greater oxidant load accounts for the greater decrease in TAS in patients with pneumonia as compared to patients with asthma. The dissimilar cellular background may also contribute to this difference, provided that neutrophil activity and the process of "respiratory burst" are prominent in the pathogenesis of pneumonia.

 

A probable limitation of the present study is failure to provide information about the reproducibility of measurements. However, the study of patients with disease exacerbation (asthma) or acute disease (pneumonia) entails an inherent difficulty in obtaining repeat measurements since both clinical and laboratory findings change dramatically day by day.
Conclusively, the present study demonstrated that the total antioxidant status in blood serum was decreased in severe asthma exacerbation and community acquired-pneumonia at disease onset; this finding confirms our initial assumption that increased oxidative stress would have an impact on total antioxidant defense. The correlation of the observed change in total antioxidant status with the severity of asthma or pneumonia, along with the simultaneous improvement in clinical and laboratory findings, and antioxidant activity suggest that the change in TAS is not an epiphenomenon; rather, it is directly related to the pathophysiological processes and the course of these conditions. Further studies are required to investigate:
a. which antioxidants play key roles in the outcome of asthma exacerbation or community-acquired pneumonia;
b. the nature of the local antioxidant defense in target-organs (bronchi or alveoli for asthma and pneumonia, respectively);
c. the utility of treatment with antioxidants for either prevention or improved outcome in these conditions.

 

 

 

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