Chronic Obstructive Pulmonary Disease (COPD) is defined as a disease characterized by persistent, progressive airflow limitation. Recent studies have underlined that COPD is correlated to many systemic manifestations, probably due to an underlying pattern of systemic inflammation. In COPD fractional exhaled Nitric Oxide (FeNO) levels are related to smoking habits and disease severity, showing a positive relationship with respiratory functional parameters. Moreover FeNO is increased in patients with COPD exacerbation, compared with stable ones. In alpha-1 antitrypsin deficiency, a possible cause of COPD, FeNO levels may be monitored to early detect a disease progression. FeNO measurements may be useful in clinical setting to identify the level of airway inflammation,
As is well known, chronic obstructive pulmonary disease (COPD) is simply considered a lung disease characterised by the presence of fixed and progressive airflow limitation derived from airway inflammation/remodelling associated with parenchymal destruction so-called pulmonary emphysema. However, in most of COPD patients the disease coexists with several other systemic manifestations which can make health-related quality of life worse and increase mortality [
The best-recognised comorbidities in COPD include lung cancer, cardiovascular diseases, malnutrition involving primarily the loss and dysfunction of skeletal muscles, osteoporosis, anaemia, diabetes, increased gastroesophageal reflux, metabolic syndrome, obstructive sleep apnoea, depression, and anxiety. Comorbidities can be classified in conditions that share pathogenetic mechanisms with COPD (e.g., smoking-related diseases such as ischemic heart disease and lung cancer), conditions that complicate COPD (such as osteoporosis and sarcopenia), and conditions that are simply associated with COPD for epidemiologic reasons (like glaucoma and obstructive sleep apnoea) [
In COPD patients, the high frequency of concurrent diseases may be largely explained by the old age of the majority of patients and by cigarette smoke exposure, the major risk factor for COPD, many other chronic diseases, and certain cancers. Smoking triggers a local inflammatory response throughout the whole tracheobronchial tree, and pathologic changes, a characteristic of COPD, are found in the proximal large airways, peripheral small airways, lung parenchyma, and pulmonary vasculature [
Furthermore, one-half of all people aging more than 65 years have at least three chronic medical conditions, and aging itself is associated with a chronic low-grade inflammatory status [
Endogenous nitric oxide (NO) is a gaseous signaling molecule produced by residential and inflammatory cells in both large and peripheral airways/alveoli. NO plays an important role in regulating airway and vascular function and is generated by three isoforms of NO synthases (neuronal NOS (nNOS, NOS1), endothelial NOS (eNOS, NOS3), and inducible NOS (iNOS, NOS2)) with different expression and pathophysiologic roles in the airways. In particular, iNOS is not constitutively expressed but is induced by several stimuli including endogenous mediators (chemokines and cytokines) and exogenous factors (bacterial toxins, viral infection, allergens, environmental pollutants, etc.) [
Corticosteroids directly suppress iNOS in rodent cells but do not directly inhibit iNOS expression in human airway epithelial cells [
Oxidative stress generates superoxide anions and in combination with NO may result in the formation of the highly reactive species peroxynitrite, which is increased in exhaled breath condensate and airway mucosa of COPD patients [
FeNO measurements have been considered a surrogate for eosinophilic airway inflammation, especially in asthma. In most mild asthmatics, high FeNO at 50 mL
FeNO levels in COPD are conflictual [
Trend of FeNO levels in COPD and related comorbidities.
Disease/condition | FeNO levels |
---|---|
Smoking habit |
|
Severe COPD |
|
Stable COPD | = |
Exacerbation of COPD | ↑ |
AAT deficiency PiZZ |
|
AAT deficiency PiMZ | ↑ |
PAH |
|
Systemic sclerosis | ↑ |
Decompensated HF | ↑ |
After exercise in stable HF | ↑ |
Atherosclerosis |
|
Psoriasis | ↑ |
↑: >20 ppb; =: 10–20 ppb;
In COPD patients, the magnitude of the NO signal is considerably less than in asthma and, most importantly, the major causative agent, cigarette smoke, dramatically masks any tendency towards a disease related rise in exhaled NO levels. This may have consequences not only for monitoring patients with COPD, but also for the natural history and prognosis of the disease. The positive relationship between exhaled NO levels and FEV1 is in keeping with the hypothesis that endogenous NO represents an important protective mechanism. This could be particularly relevant in patients with COPD who may require local NO release for antimicrobial host defence or preservation of ventilation/perfusion matching within the lung [
Several studies [
In conclusion, in COPD the role of FeNO monitoring to therapeutic intervention is still unclear with respect to clinical relevance in particular because of the absence of randomized, double blind, control studies.
Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder due to homozygosity or heterozygosity for the protease inhibitor (Pi) Z allele, and these two genetic phenotypes are, respectively, characterized by a severe reduction (PiZZ) and a lower reduction (PiMZ) of plasma levels of AAT than in normal subjects. The homozygotic form of the disease is considered to be an important risk factor for developing COPD [
Severe AAT deficiency (PiZZ) is characterized by lower FeNO level (Table
Pulmonary arterial hypertension (PAH) is characterized by an elevation of the pulmonary arterial pressure and an increased pulmonary vascular resistance, leading to decline in cardiopulmonary function and premature death [
PAH is commonly caused by an underlying pulmonary or systemic disease, whilst idiopathic PAH (IPAH) is referred to PAH when diagnosed in the absence of an identifiable cause or disease.
IPAH is the most studied form of PAH, characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, and thrombosis in situ [
Systemic sclerosis (SSc) is a connective tissue disorder of unknown etiology, characterized by a multisystemic involvement, and that is often complicated by pulmonary involvement [
It has been hypothesized that NO provides an important role in heart failure (HF) in either the pathogenesis or disease progression, although the precise role played by NO is complex [
In patients with chronic HF, deregulated systemic NO production due to endogenous inhibitors of NO synthases such as asymmetric dimethylarginine (ADMA) has been related to both systolic and diastolic dysfunction in addition to poor long-term adverse outcomes [
Several studies in symptomatic HF patients at rest have reported variable FeNO levels compared with normal control subjects, and the results in literature are conflicting. Higher levels of FeNO were observed in decompensated HF resting (Table
Patients who fail to raise FeNO during exercise have been related to a higher long-term mortality rate [
As mentioned above, several FeNO studies have shown conflicting results regarding FeNO levels at rest and exercise. These contradictory reports can probably be explained by the difference in the populations studied and the use of different techniques for FeNO analysis; moreover the type of cardiomyopathy is rarely reported, and it can be hypothesized that ischemic heart disease could be much different in terms of NO production than idiopathic dilatative heart disease. However, more recent reports seem to indicate that FeNO levels increased after exercise in chronic compensated HF patients [
Endothelial NO seems to play a key role in the atherogenic process platelet adhesion and aggregation, expression of adhesion molecule and chemokine production, and inflammatory cell infiltration together with smooth muscle cell migration and proliferation [
This central balancing function of NO is hindered during the atherosclerotic process, in which endothelial damage causes the decline in bioactivity of endothelial nitric oxide synthase and consequently impaired release of NO. Furthermore, ischemic heart disease (IHD) is characterized by a low-grade systemic inflammation and associated with increased oxidative stress; these factors enhance the inactivation of NO at endothelial level in the arterial wall and could lead to diminished systemic bioavailability of NO [
Psoriasis vulgaris is a multisystem common dermatologic disease characterized by chronic inflammatory pathogenesis [
Recent developments described psoriasis pathophysiology as mainly directed by Th1 and Th17 cells which provoke a skin barrier dysfunction [
New evidence concerning FeNO in relation to COPD and the best-recognized comorbidities collectively highlights the following potential roles of this biomarker in monitoring (1) the stability of COPD; (2) the response to therapy in heart failure and in PAH patients; (3) the possible progression to COPD of other diseases like alpha-1 antitrypsin deficiency and psoriasis. These latter aspects may be useful to integrate the clinical evaluation of patients with COPD and comorbidities.
Since FeNO levels are strongly affected by cigarette smoking and many COPD patients are current smokers, the usefulness of FeNO measurement can be limited. In COPD patients, the role of add-on FeNO monitoring to therapeutic intervention is less clear with respect to clinical benefits, especially in the absence of conclusive double-blind, randomized, control studies. Therefore, routine monitoring of FeNO in COPD is less established than in asthma as noted in the recent ATS Clinical Guidelines.
Nitric oxide
Nitric oxide synthase
Neuronal NOS
Inducible NOS
Endothelial NOS
Exhaled nitric oxide fraction
American Thoracic Society
Corticosteroids
Chronic obstructive pulmonary disease
Cystic fibrosis
Alpha-1 antitrypsin
Systemic sclerosis
Pulmonary arterial hypertension
Interstitial lung disease
Heart failure
Ischemic heart disease
Psoriasis
Psoriasis area severity index
Forced expiratory volume in the 1st second.
The authors declare that there is no conflict of interests regarding the publication of this paper.