BIOMARKERS in OBSTRUCTIVE DISEASEBIOMARKERS in OBSTRUCTIVE DISEASE
Firat University, Department of Chest Disease
Presentation Plan
Serum
Definition
Biomarker is a physical sign or laboratory measurement that is evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to therapeutic interventions
It is helpful in evaluating the;
Activity of the disease
Prognosis
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Minimally invasive, easily measurable and reproducible
Used in confirming the diagnosis or defining a special clinic fenotype
It must show dose-response relation, must be a guide for determining the therapy needs
Used in predicting the adverse events, and clinical outcomes that will appear in the future
Why are biomarkers necessary for respiratory disease?
Tissue biopsy is rarely used in defining benign pathologies
Scanning methods and physiological measurements have limitations
The structure and functions in disease like asthma and COPD change intermittent or progressively
Because symptoms are nonspesific and multifactorial in patients with comorbidities, biomarkers are needed
Biomarkers in COPD
Biomarkers in determining the COPD occurrence risk
Low FEV1 measured at mean age 25-years old was predictive of the presence of airflow obstruction measured 20 years later independent of cigarette smoking
Kalhan R, et al. Am J Med 2010; 123: 468-e1-7
Higher CRP levels were associated with lower lung function in ages 26-32 unrelated to smoking, obesity, and asthma
Hancox RJ, et al. Thorax 2007; 62: 1064-8
Subjects 55 years of age and older, CRP was associated with increased risk of COPD
Van Durme YMTA, et al. Am J respir Crit Care Med 2009; 179: 375-82
High CRP and fibrinogen in young adulthood were both associated with accelerated decline in the FVC and FEV1 over the subsequent 13-15 years
Kalhan R, et al. Plos ONE 2010; 5:e11431
Biomarkers in the Activity, Prognosis, and Therapy Response in COPD
Pulmonary Biomarkers
Nonpulmonary Biomarkers
Bronchial biopsy
Structural changes
Cellular patterns
Expression of inflammatory proteins
Advantage of bronchial biopsies;
They can provide an assesment of structural components of the airway wall
Biomarkers of structural damage can be measured
The different inflammatory cell subtypes can be identified in their microenvironment, thus allowing investigation of interaction between inflammatory and resident cells
Limitations of bronchial biopsies;
It may be difficult to perform in studies which require repeated biopsies
It may be difficult to perform in patients with cardiac comorbidity, significant hypercapnia, and desaturation
The biopsy of proximal airways may not closely reflect all the pathologic changes present in peripheral airways and lung parenchyma
There is a relativelly high variability in baseline measurements of inflammatory cells, which necessitates multiple biopsies
In stable COPD;
There is increased infiltration of CD8+ T lymphocytes and macrophages
Barnes P, et al. Am J Respir Crit Care Med 2006; 174: 6-14
Chemokine receptor expression related with type-1 response is seen
Saetta M, et al. Am J Respir Crit Care Med 2002; 165: 1404-09
Prominent neutrophilia is present in the airway lumen, tissue neutrophil number increases with severity of disease
Di Stefano A, et al. Am J Respir Crit Care Med 1998; 158: 1277-1285
The number of IL-22+, IL-23+ immunoreactive cells is increased in the bronchial epitelium
In all smokers and in patients with COPD, the number of IL-22+ cells correlated with the number of CD4+ and CD8+ cells in the bronchial mucosa
Endothelial cells express high levels of IL-17A and IL-22
Di Stefano A, et al. Clin Exp Immunol 2009; 157: 316-24
Smokers with COPD had elevated levels of YKL-40 in serum and BAL, more YKL-40-positive cells in bronchial biopsies than smokers without COPD or never-smokers
YKL-40 levels in serum and BAL were associated with airflow obstruction and impaired diffusion lung capacity
Letuve S, et al. J Immunol 2008; 181: 5167-73
Increased expression of NF-KB in bronchial biopsies from smokers and patients with COPD
Di Stefano A, et al. Eur Respir J 2002; 20: 556-63
Altered surfactant protein-A expression in type II pneumocytes in COPD
Vlachaki EM, et al. Chest 2010; 137: 37-45
Pulmonary surfactant protein A (SP-A) is a lectin, with multiple functions that contribute to innate host defense and the regulation of the inflammatory process in the lung. In normal conditions, SP-A seems to protect against the effects of smoking
higher SP-A levels in control nonsmokers (4.8 +/- 0.05) when compared with patients with COPD (0.6 +/- 0.7) and smokers without COPD
differences that were not statistically significant were observed in SP-A levels among the patients with COPD and the smokers without COPD
The immunohistochemical examinations showed an increase in the overall number of type II pneumocytes per high-power field in patients with COPD, but a decreased ratio of SP-A positive type II pneumocytes to total type II pneumocytes, compared with smokers without COPD
This ratio was also correlated with FEV(1)
The ratio of SP-A positive alveolar macrophages was increased in patients with COPD when compared with smokers without COPD (P = .002), while this was correlated with airway obstruction (FEV(1), % pred)
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Accumulation of eosinophils increase
Saetta M, et al. Am J Respir Crit Care Med 1994; 150: 1646-1652
Zhu J, et al. Am J Respir Crit Care Med 2001; 164: 109-116
Qiu Y, et al. Am J Respir Crit Care Med 2003; 168: 968-75
Inhaled steroids decrease the number of attacks by decreasing the number of mast cells, but have a little effect on airway inflammation
Hattotuwa KL, et al. Am J Respir Crit Care Med 2002; 165: 1592-96
Verhoeven GT, et al. Thorax 2002;57:694–700
Antiinflammatory effects of salmeterol/fluticasone propionate in COPD
140 moderate-severe COPD (current smoker or ex smoker)
13 week placebo/ SALM/FP(50-500 mikrogr)
Bronchial biopsies obtained at baseline and at Week 12
Barnes NC, et al. Am J Respir Crit Care Med 2006; 173(7):736-43.
Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast in COPD
59 COPD patients
Bronchial biopsies obtained at baseline and at Week 10
CD8
CD68
Gamble E, et al. Am J Respir Crit Care Med 2003; 168: 976-82
BAL
Advantage;
It is usually a safe procedure
When performed with bronchial biopsy, it can provide additional information
Limitations;
It is an invasive procedure
It may cause transient fever
The return of fluid is often reduced in patients with COPD
Quantification of biomarkers in supernatant is a problem
Cellular composition;
The cellular composition in individuals with COPD is predominantly alveolar macrophages (>80%)
Smoking is associated with increased numbers of neutrophils
Lymphocytes are generally higher in ex-smokers than in smokers
Some patients with COPD have higher eosinophil percentages than healthy smokers
Cazzola M, et al. Eur Respir J 2008, 31: 416-69
The percentage of CD8+ T lymphocytes is higher in COPD and healthy smokers compared with healthy non-smokers
The percentage of CD4+ T cells is lower in COPD
Hodge G, et al. Clin Exp Immunol 2007; 150: 22-9
Tissue culture of macrophages from patients with COPD shows increased expression of inflammatory proteins, such as TNF-α, IL-8, matrix metalloproteinase (MMP)-9
Culpitt SV, et al. Am J Respir Crit Care Med 2003;167(1):24-31
Russell RE, et al. Am J Respir Cell Mol Biol 2002;26(5):602-9
Inflammatory Mediators;
Levels of eosinophil cationic protein, myeloperoxidase, and IL-8 are increased in patients with COPD compared with healthy nonsmokers
Barnes P, et al. Am J Respir Crit Care Med 2006; 174: 6-14
Patients with COPD had higher levels of tryptase and histamine
Kalenderian R. Chest 1988;94:119-123
Total elastase activity is increased, and antielastase activity decreased in patients with COPD when compared with healthy smokers
Fujita J. Am Rev Respir Dis 1990;142:57-62
BAL and epithelial cell CD8+ T cell numbers were inversely associated with FEV1
Hodge G, et al. Clin Exp Immunol 2007; 150: 22-9
Soler N, et al. Eur Respir J 1999; 14: 1015-22
ECP and eotaxin-1 levels were positively associated with broncodilator response and the extent of radiographic emphysema
Miller M, et al. J Allergy Clin Immunol 2007; 120: 1118-25
In the BAL fluid compartment of COPD patients, total lipid metabolite amount (particularly PGD2 and eicosapentaenoic acid) show a remarkable linear correlation with lung function
Csanky E, et al. Electrophoresis 2009; 30: 1228-34
Sputum
Many patients can not expectorate spontaneously
So induced sputum is prefered
Limitations of induced sputum
Sputum induction induces transient neutrophilia, an longtime eosinophilia
Repeated induction must be made after 48 hour
Solubilization of sputum with dithiothreitol inhibits the recognition of proteins, some cytokines and chemokines by antibodies
Proteases in sputum may degrade certain protein mediators
Cellular composition;
CD8+ T cells are increased in induced sputum of patients with COPD
Tzanakis N, et al. Respir Med 2004;98:57-65
The percentage of neutrophiles increased typically in induced sputum of patients with COPD
Dragonieri S, et al. Monaldi Arch Chest Dis 2009; 71: 119-26
Sputum percentage of neutrophiles increases with smoking, and progression of disease
Perng DW, et al. Chest 2004; 126: 375-81
Some COPD patients show an increased number of eosinophils, this seems to predict a better response to bronchodilators and inhaled corticosteroids
Papi A, et al. Am J Respir Crit Care Med 2000; 162: 1773-7
Inflammatory Mediators;
Sputum IL-8 is increased in patients with COPD compared with smokers
It is related to disease severity
Franciosi LG, et al. Pulm Pharmacol Ther 2006; 19: 189-99
TNF-α concentrations increased in sputum of COPD patients when compared with healthy smokers
Vernooy JH, et al. Am J Respir Crit Care Med 2002; 166: 1218-1224
The levels of inflammatory mediators involved in neutrophil recruitment (GROα, LTB4, neutrophil elastase, monocyte chemotactic protein-1, human neutrophil lipocalin, myeloperoxidase) are increased in sputum of patients with COPD
Barnes P, et al. Am J Respir Crit Care Med 2006; 174: 6-14
8-Isoprostane as a marker of oxidative stress in nonsymptomatic cigarette smokers and COPD
Kinnula VL, et al. Eur Respir J 2007; 29: 51-5
Interleukin-18 in induced sputum: association with lung function in COPD
Rovina N, et al. Respir Med 2009; 103: 1919-25
Apolipoprotein A1 and lipocalin-1 reduced in patients with COPD when compared with healthy smokers
They are correlated with the severity of COPD, and it has been suggested that their reduction indicates a deficient innate defence system in airways disease
Nicholas BL, et al. Am J Respir Crit Care Med 2010;181(10):1049-60
The levels of of neutrophil elastase, MMP-1, 8, 9, and 12 increased in the sputum of COPD patients
MMP-8 concentrations and MMP-9 activity correlate negatively with FEV1, and are positively correlated with the number of neutrophils
Hill AT, et al. Am J Respir Crit Care Med 1999; 160: 893-898
Beeh KM, et al. Respir Med 2003; 97:634-639
Vernooy JH, et al. Chest 2004; 126: 1802-1810
Culpitt SV, et al. Respir Med 2005; 99: 703-710
Demets IK, et al. Thorax 2006; 61: 196-201
No differences in the concentrations of the tachykinins, subtance P, and neurokinin A were found between patients with COPD, normal smokers, and nonsmokers, although there was a reduction in tachykinins during exacerbations of COPD
Boschetto P, et al. Pulm Pharmacol Ther 2005; 18: 199-205
The expression of urokinase-type plasminogen activator receptor (uPAR) on induced sputum neutrophils and macrophages was significantly higher in COPD patients compared with healthy non-smokers and healthy smokers
Sputum uPAR and human cationic antimicrobial protein 18 (CAP18) levels showed significant inverse correlations with FEV1% and 6MWD, and significant positive correlations with St. George’s Respiratory Questionnaire scores
Jiang Y, et al. Respirology 2010; 15: 939–946
A meta-analysis showed that at least 6 weeks of inhaled corticosteroid therapy results in a reduction of the sputum neutrophil count in patients with stable COPD
Gan WQ, et al. Chest 2005; 127: 558-64
Erythromycin was associated with significantly reduced sputum neutrophilia after 6 months and was accompanied by a reduction in COPD exacerbation
He ZY, et al. Respiration 2010; 80: 445-52
Induced sputum neutrophils was significantly reduced by about 22% by theophylline
Culpitt S, et al. Am J Respir Crit Care Med 2002; 165: 1371-6
N-alpha-PGP and PGP, potential biomarkers and therapeutic targets for COPD
O’Reilly P, et al. Respir Res 2009; 10: 38
Exhaled Biomarkers
Repeated sampling can be done
Inflammation in the peripheral airways can be assessed
Nitric Oxide;
In COPD, conventionally measured fraction of FeNO does not seem to be useful
The levels are usually normal or only slightly elevated, except during exacerbations
Barnes P, et al. Am J Respir Crit Care Med 2006; 174: 4-14
eNO levels were shown to be raised in both smoking and ex-smoking COPD patients relative to healthy non-smokers
Liu J, et al. Respiration 2007; 74: 617-23
While bronchial NO is low or normal in COPD, there is an increase in alveolar NO that is related to disease severity; this may reflect the increase in iNO syntase inthe lung periphery
MEFT FENO measurements can be used for COPD monitoring
Because;
Brindicci C, et al. Eur Respir J 2005; 26: 52-59
Bacterial colonisation in the lower airways of stable COPD patients increases airway inflammation
Level of alveolar NO, that do not response to the antibacterial theraphy, can predict that clinic course will be bad
Kharitonov SA, et al. Chest 2006; 130: 1541-1546
An increase in FENO in patients with COPD is correlated with increased numbers of eosinophils, an increased bronchodilator and steroid response
Papi A, et al. Am J Respir Crit Care Med2000;162:1773-7
Levels of FENO can be low in COPD patients who has pulmonary hypertension, and cor pulmonale
This finding can be helpful for determining the patients who can benefit from LTOT
Clini E, et al. Am J Respir Crit Care Med 2000; 162: 446-50
Croxton TL, et al. Am J Respir Crit Care Med 2006; 174: 373-8
Carbon Monoxide;
Exhaled CO is increased in COPD patients, but it is also increased in healthy smokers
Levels of eCO increases during COPD exacerbations
Montuschi P, et al. Chest 2001; 120: 496-501
Hydrocarbons;
Volatile hydrocarbons are biomarkers of lipid peroxidation as a result of oxidative stress
Concentrations of ethane are elevated in patients with COPD, and correlated with disease severity
Paredi P, et al. Am J Respir Crit Care Med 2000; 162: 369-373
Exhaled Breath Condensate
Limitations of procedure;
Low levels of concentrations of measured mediators
Hydrogen peroxide;
H2O2 is increased in EBC of patients with COPD, is further increased during exacerbations
Dekjuijzen PNR, et al. Am J Respir Crit Care Med 1996; 154: 813-816
Levels of H2O2 is related to FEV1, number of neutrophils, and dyspnea score, so it reflects disease activity
Kostikas K, et al. Chest 2003; 124: 1373-1380
Hidrojen peroksid
8- isoprostan;
It is the most reliable biomarker of oxidative stress in humans
Smoking habit does not seem to affect 8-isoprostan levels in EBC in patients with COPD
Concentrations of 8-Isoprostane are greater in EBC of patients with COPD than in normal smokers, are related to disease severity
Montuschi P, et al. Am J Respir Crit Care Med 2000; 162: 1175-1177
Ko FW, et al. Respir Med 2006, 100: 630-638
8-isoprostan EBC levels are significantly correlated with the extent of emphysema as measured by HRCT, and with dyspnea
Makris D, et al. Respiration 2008; 75: 138-44
8- isoprostan ataklar srasnda daha da artar
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EBC LTB4 is correlated with sputum neutrophilia
It may be a useful biomarker of the degree of neutrophilic inflammation
Kostikas K, et al. Chest 2005; 127: 1553-9
Levels of MDA are greater in EBC of patients with COPD than in normal smokers
Corradi M, et al. Am J Respir Crit Care Med 2003; 167: 1380-1386
Increased nitrative stress in COPD is indicated by increased concentration of nitrite and nitrosothiols
Corradi M, et al. Am J Respir Crit Care Med 2001; 163: 854-858
pH;
It is the most extensively studied EBC biomarker
EBC pH of patients with COPD is low, and significantly more variable
A subset of COPD patients exhibit a very low pH in EBC which may be indicative of a spesific COPD phenotype
Kostikas K, et al. Am J Respir Crit Care Med 2002; 165: 1364-1370
Borrill Z, et al. Eur Respir J 2005; 25: 269-74
In EBC of COPD patients;
Levels of PGE2, and PGF2α significantly increased
Level of LTE4 is normal
Concentrations of LTB4 is high, and correlated with sputum neutrophilia
Montuschi P, et al. Thorax 2003; 58: 585-588
Kostikas K, et al. Chest 2005; 127: 1553-9
Plasma
CRP;
CRP is raised in COPD independently of other factors (smoking, comorbidities)
Pinto-Plata VM; et al. Thorax 2006; 61: 23-8
Increases in CRP over time are associated with decreases in FEV1
Shaaban R, et al. Respir Med 2006, 100: 2112-20
Increased baseline CRP is associated with subsequent risk of hospitalisation and mortality
Dahl M, et al. Am J Respir Crit Care Med 2007; 175: 250-5
Fibronectin/CRP ratio was found to be independently associated with mortality after more than 7 years of follow-up
Man SFP, et al. Eur Respir J 2008; 32: 1451-7
High sensitivity-CRP has been identified as an early marker of inflammation that is significantly increased in the circulation even in mild COPD
Piehl-Aulin K, et al. Respiration 2009; 78: 191-6
Fibrinogen;
Patients with high plasma levels of fibrinogen and neutrophil counts had a faster % predicted FEV1 decline
Donaldson GC, et al. Chest 2005; 128: 1995-2004
Walter RE, et al. Chest 2008; 133: 19-25
Individuals with baseline plasma fibrinogen of more than 3.3 g/L had reduced lung function, and an increased risk for hospitalisation
Dahl ML; et al. Am J Respir Crit Care Med 2001; 164: 1008-11
During exacerbations of COPD, higher levels of fibrinogen are seen, and they decline with exacerbation recovery, but it contributes increase in cardiovasculary mortality and morbidity
Wedzicha JA, et al. Thromb Haemost 2000; 84: 210-5
Plasma fibrinogen rose faster over time in patients with COPD who had more frequent exacerbations
Donaldson GC, et al. Chest 2005; 128: 1995-2004
Raised levels of inflammation-sensitive plasma proteins (fibrinogen, ceruloplasmin, α1-antitrypsin, haptoglobin, orosomucoid) predicted hospital admissions for COPD
Engstrom G, et al. Thorax 2009; 64: 211-5
SP-D;
Levels of serum SP-D were higher in the mixture of current and former smokers with COPD compared to those without COPD, and in smokers compared to non-smokers with no airflow obstruction
Lomas DA, et al. Eur Respir J 2009; 34: 95-102
Changes in serum SP-D levels tracked well with changes in health status over a 3 month period in patients with severe COPD
Sin DD, et al. BMC Pulm Med 2007; 7: 13
Markers of T cell and eosinophilic inflammation can show COPD progression
Levels of plasma IL-2 is increased in patients with stable disease
Disease progression is rapid in patients whose plasma eotaxin-1 level is high
D’Armiento JM, et al. Respir Res 2009; 10: 113
High concentrations of PARC/CCL-18 were associated with the presence of COPD and mortality in COPD
Sin DD, et al. Am J Respir Crit Care Med 2011; 183: 1187-92
Plasma concentrations of desmosine was significantly associated with FEV1 and DLCO
Lindberg CA, et al. Eur Respir J 2011 (in press)
Levels of SAA increased during exacerbations
Bozinovski S, et al. Am J Respir Crit Care Med 2008; 177: 269-78
Copeptin level>40 pmol/L had a significantly longer hospital stay and higher hospital mortality
Stolz D, et al. Chest 2007; 131: 1058-67
Serum levels of TNF-α , and IL-6 are high in stable COPD, further increased during exacerbations
Karadag F, et al. Lung 2008; 186:403–409
Increase in IL-6 levels is related to decrease in FEV1, and exercise capasity
Yende S, et al. Thorax 2006; 61: 10-16
BIOMARKERS in ASTHMA
Bronchial Biopsy
Asthmatic airways have increased granulation of mast cells and high affinity IgE receptor bearing cells
Laberge S, et al. Int Arch Allergy Immunol 1999; 119:120-125
Enhanced IL-8 and IFN-γ expression, also IL-5 and eotaxin expression and reduced IL-4 expression of severe asthma is reported
Shannon J, et al. Chest 2008; 133:420-426
Steroids and other anti-inflammatory interventions have been shown to reduce T-cell and eosinophil infiltration of the lamina propria
Bentley AM, et al. Am J Respir Crit Care Med 1996; 153:551-556
BAL
Patients with moderate asthma not treated with corticosteroids have higher percentages of eosinophils
In severe steroid resistant asthma, a neutrophil predominant phenotype is noted
Moore WC, et al. J Allergy Clin Immunol 2007; 119:405-413
BAL fluid from asthmatic patients shows increased amounts of eotaxin, and the CCR4 chemokine receptor ligand, MDC
Lamkhioued B, et al. J Immunol 1997; 159: 4593-4601
Lezcano-Meza D, et al. Allergy 2003; 58: 1125-1130
BAL from patients with status asthmaticus contains large numbers of neutrophils, with an increase in neutrophil elastase, and elevated levels of both pro-inflammatory and antiinflammatory cytokines
Itillie-Leblond I, et al. Am J Respir Crit Care Med 2000; 162: 586-592
Tonnel A, et al. Int Arch Allergy Immunol 2001; 124: 267-271
Induced Sputum
Number of eosinophils, and neutrophils in severe persistant asthma increased related to severity of disease
Louis R, et al. Allergy 2002; 57: 907-12
Louis R, et al. Am J Respir Crit Care Med 2000; 161: 9-16
Number of sputum eosinophils is the best predictor for steroid response
Brightling CE, et al. Treat Respir Med 2005; 4: 309-16
Levels of eosinophilic cathionic protein is related to number of eosinophil in asthmatic patients
EfthimiadisA, et al. Eur Respir J 1997; 10: 1336-40
Antiinflammatory treatment reduced both eosinophil number and levels of ECP in airway
Perng DW, et al. Chest 2004;125: 1693-9
Levels of MMP-9 increased in sputum of astmatic patients
Boulay ME, et al. Respiration 2004; 71: 216-24
Increase in MMP-9 /TIMP ratio is correlated with disease severity
Cataldo DD, et al. Chest 2002; 122: 1553-9
Level of IL-8 increased in asthma attacks, and in severe disease
Gibson PG, et al. Chest 2001; 119: 1329-36
Norzila MS, et al. Am J Respir Crit Care Med 2000; 161: 769-74
Levels of cysteinyl leukotriens increased in the sputum of asthmatic patients
McFarlane AJ, et al. Am J Respir Crit Care Med 2000; 161: 1553-8
Pavord ID, et al. Am J Respir Crit Care Med 1999; 160: 1905-9
Levels of 8-isoprostan increased in severe persistant asthma and during attacks
Wood LG, et al. Am J Respir Crit Care Med 2005; 171: 436-40
Expression of IL-4, 5, and 13 increased in sputum of asthmatic patients, and inhaled steroids could supress this increase
De Klujver J, et al. Am J Respir Crit Care Med 2002; 166: 294-300
Truyen E, et al. Thorax 2006; 61: 202-8
TNFα has been found to correlate even more strongly with airway hyperreactivity in severe asthma than do eosinophil and ECP levels
Obase Y, et al. Ann Allergy Asthma Immunol 2001; 86: 304-310
Anti TNFα therapy produced improvements in FEV1 and AHR
Berry M, et al. Am J Respir Crit Care Med 2005; 171: A569
Exhaled Biomarkers
Concentration of H2O2 in EBC increased in patients with severe asthma
Antczak A, et al. Respir Med 2000; 94: 416-21
Van Hoydonck PGA, et al. Eur Respir J 2004; 23: 189-92
Exhaled H2O2 correlated negatively with FEV1 and PC20 histamine concentrations in patients with uncontrolled allergic asthma
Emelyanov A, et al. Chest 2001; 120: 1136-9
Inhaled steroids decreased the level of exhaled H2O2, and increased FEV1 levels
Antczak A, et al. Respir Med 2000; 94: 416-21
Levels of cysteinyl leukotrienes increased with disease severity, and decreased with antiinflammatory drugs
Czoma Z, et al. Am J Respir Crit Care Med 2002; 166: 1345-9
Baraldi E, et al. Thorax 2003; 58: 505-9
Levels of 8-isoprostan is related to disease severity
Montuschi P, et al. Am J Respir Crit Care Med 1999; 160: 216-20
Levels of 8-isoprostan do not supress fully with steroids, so it can be a well marker of airway inflammation despite the antiinflammatory therapy
Montuschi P, et al. Methods Mol Biol 2010; 594: 73-84
pH of EBC is 7.8 in healthy individuals, in asthmatic patients it is <7.5
Kostikas K, et al. Am J Respir Crit Care Med 2002; 165: 1364-70
Carpagnano GE, et al. Chest 2004; 125: 2005-10
Levels of pH decreased more over during attacks, and increased with steroid therapy
Hunt JF, et al. Am J Respir Crit Care Med 2000; 161: 694-9
Exhaled NO
Increase in FENO has a >90% specifity in asthma diagnosis
Dupont LJ, et al. Chest 2003; 123: 751-756
de Jongste, et al. Paediatr Respir Rev 2000; 1: 354-360
Its sensitivity can be decreased by inhaled steroids
Normal levels of FENO can distingusih asthmatic patients from patients with chronic nonasthmatic cough
Barnes PJ, et al. Chest 2006; 130: 1541-1546
Increase in the level of eNO is related to decrease in asthma control
Jones SL, et al. Am J Respir Crit Care Med 2001; 164: 738-43
Alveolar NO levels is high in severe asthma when compared with mild-moderate persistant asthma
Berry M, et al. Eur Respir J 2005; 25: 986-91
Inhaled steroids, LTRA, and omalizumab decreased level of eNO both in children and adults
Straub DA, et al. Eur Respir J 2005; 25: 289-94
Kharitonov SA, et al. Thorax 2002; 57: 889-96
Alveolar NO is resistant to inhaled steroids, responsive to oral steroids
Berry M, et al. Eur Respir J 2005; 25: 986-91
High levels of alveolar NO is related to morbidity and worse asthma control independent of spirometry, and atopy in children with asthma
Puckett JL, et al. Respir Res 2010; 28: 1213-20
Low levels of eNO can predict to decrease inhaled steroids succesfully
Taylor DR, et al. Thorax 2006; 61: 817-27
Airway hyperreactivity and number of asthma attacks, in which oral steroids are used, decreased when theraphy is ordered upon levels of eNO
Pijnenburg MW, et al. Am J Respir Crit Care Med 2005; 172: 831-6
Carbon monoxide;
CO level is normal or minimally increased in mild asthma, but higher levels are found in severe disease
Stirling R, et al. Am J Respir Crit Care Med 2000; 161: A922
Electronic nose (eNose): exhaled molecular profiles
Volatile organic compounds in exhaled air may be used to monitor pulmonary disease
Standard technique is gas chromatography coupled to mass spectrometry
This technique is suitable for pathophysiological research
Breath collection is critical for eNose assessments, includes standardization of expiratory flow, expired volume, and water vapour
J Allergy Clin Immunol 2007;120:856-62
Serum
Number of blood eosinophils is often high in patients with asthma
Schatz M, et al. Arch Intern Med 1982; 142: 1515-9
Blood eosinophil number is correlated positively with symptom score, and correlated negatively with FEV1
Bousquet J, et al. N Engl J Med 1990; 323: 1033-9
Ulrik CS, et al. Clin Exp Allergy 1995; 25: 820-7
Levels of ECP and EPO increased during attacks
Parra A, et al. J Invest Allergol Clin Immunol 1999; 9: 27-34
Levels of eotaxin, IL-4, and IL-5 increased
Tateno H, et al. Respir Med 2004; 98: 782-90
Leung T, et al. Clin Exp Allergy 2004; 34: 786-91
Blood level of total IgE is high in some patients
Siroux V, et al. Clin Exp Allergy 2003; 33: 746-51
Presence of allergen spesific IgE is a marker of atopic asthma
Szefler SJ, et al. J Allergy Clin Immunol 2012; 129: 9-23
Increase in serum spesific IgE levels is related to decrease in lung functions
Simpson A, et al. J Allergy Clin Immunol 2005; 116: 744-9
Urine
Urine LTE4 is a marker of cysteinyl leukotriene activity
Levels of urine LTE4 increased during asthma attacks, and in nocturnal asthma at nights
Green SA, et al. Thorax 2004; 59: 100-4
Levels of urine LTE4, in severe asthma that occured after 12 years, is higher than early onset, and aspirin-induced asthma
Miranda C, et al. J Allergy Clin Immunol 2004; 113: 101-8
BIOMARKERS in CYSTIC FIBROSIS
BAL and bronchial washing is accepted as gold standard in evaluating of inflammation and enfection in CF
Prominent cells in the airways of patients with CF is neutrophils
Sagel SD, et al. Proc Am Thorac Soc 2007; 4: 406-17
Number of sputum neutrophil, and level of neutrophil elastase is correlated with FEV1
Mayer-Hamblett N, et al. Am J Resp Crit Care Med 2007;175:822–828
Levels of IL-1, IL-6, IL-8 v, and TNFα is increased in BAL fluid
Bonfield TL, et al. Am J Respir Crit Care Med 1995;152:2111–2118
Levels of IL-10, and NO decreased in the airways of patients with CF
Balfour-Lynn IM, et al. Arch Dis Child 1996;75:319–322
Bonfield TL, et al. J Allergy Clin Immunol 1999;104:72–78
Expression of PPAR in lung tissue is decreased
Ollero M, et al. J Cell Physiol 2004;200:235–244
Sputum levels of zinc, copper and iron were elevated in patients with CF
Zinc decreased following treatment of CF exacerbation
In subjects with CF sputum zinc levels correlated with MPO and IL-8 levels
Gray RD, et al. Chest 2010; 137: 635-41
Blood levels of antipseudomonal antibody, neutrophil elastase α1-antiprotease complex, and CRP is increased
Ratjen F, et al. Pediatr Pulmonol 2007;42:249–255
Downey DG, et al. Pediatr Pulmonol 2007;42:216–220
Levy H, et al. Pediatr Pulmonol 2007
In Conclusion
8-isoprostan is the most reliable biomarker of oxidative stress in humans
The percentage of neutrophiles increased typically in induced sputum of patients with COPD
CRP levels have been shown to predict risk of hospitalisation and death from COPD
Measurements of sputum eosinophils and exhaled NO in asthmatics are the best established markers for disease activity and response to anti-inflammatory therapy
BAL and bronchial washing is accepted as gold standard in evaluating of inflammation and enfection in CF