Exhaled nitric oxide

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Chemical formula of nitric oxide (NO) together with its molecular size (115 pm). Nitric-oxide-2D.png
Chemical formula of nitric oxide (NO) together with its molecular size (115 pm).

In medicine, exhaled nitric oxide (eNO) can be measured in a breath test for asthma and other respiratory conditions characterized by airway inflammation. Nitric oxide (NO) is a gaseous molecule produced by certain cell types in an inflammatory response. The fraction of exhaled NO (FENO) is a promising biomarker for the diagnosis, follow-up and as a guide to therapy in adults and children with asthma. The breath test has recently become available in many well-equipped hospitals in developed countries, although its exact role remains unclear.

Contents

Biology

Three-dimensional model of NO. Nitric-oxide-3D-vdW.png
Three-dimensional model of NO.

In humans, nitric oxide is produced from L-arginine by three enzymes called nitric oxide synthases (NOS): inducible (iNOS), endothelial (eNOS), and neuronal (nNOS). The latter two are constantly active in endothelial cells and neurons respectively, whereas iNOS' action can be induced in states like inflammation (for example, by cytokines). In inflammation, several cells use iNOS to produce NO, including eosinophils. As such, eNO (also known as FeNO "fractional exhaled nitric oxide") has been dubbed an inflammometer. [1]

Although iNOS is thought to be the main contributor to exhaled NO in asthmatics, [2] [3] studies in mice also point to a role for nNOS. [4] [5]

It was initially thought that exhaled NO derived mostly from the sinuses, which contain high levels of NO. It has subsequently been shown that the lower airways contribute most of the exhaled NO, and that contamination from the sinuses is minimal.[ citation needed ]

Medical use

Asthma

Patients with asthma have higher eNO levels than other people. Their levels also rise together with other clinical and laboratory parameters of asthma (for example, the amount of eosinophils in their sputum). In conditions that trigger inflammation such as upper respiratory tract infections or the inhalation of allergens or plicatic acid, eNO levels rise. [6] [7] The eNO levels also tend to vary according to the results of lung function test results such as the degree of bronchial hyperresponsiveness. Furthermore, drugs used to treat asthma (such as inhaled glucocorticoids or leukotriene receptor antagonists) also reduce eNO levels.

Clinical trials have looked at whether tailoring asthma therapy based on eNO values is better than conventional care, in which therapy is gauged by symptoms and the results of lung function tests. [8] [9] [10] To date, the results in both adults and children have been modest and this technique can not be universally recommended. [11] [12] It has also been noted that factors other than inflammation can increase eNO levels, for example airway acidity. [13] [14]

The fraction of eNO has been found to be a better test to identify asthmatics than basic lung function testing (for airway obstruction). Its specificity is comparable to bronchial challenge testing, although less sensitive. [15] [16] This means that a positive eNO test might be useful to rule in a diagnosis of asthma; however, a negative test might not be as useful to rule it out. [17]

Other conditions

The role for eNO in other conditions is even less well established compared to asthma.

Since asthma can be a cause of chronic coughing (it may even be the sole manifestation, such as in cough-variant asthma), studies have looked at whether eNO can be used in the diagnosis of chronic cough. [18] [19] [20] [21]

Exhaled NO is minimally increased in chronic obstructive pulmonary disease, but levels may rise in sudden worsenings of the disease (acute exacerbations) or disease progression. Early findings indicate a possible role for eNO in predicting the response to inhaled glucocorticoids and the degree of airway obstruction reversibility.

Children with cystic fibrosis have been found to have low eNO levels. In subjects with bronchiectasis (a state of localized, irreversible dilatation of part of the bronchial tree) not due to cystic fibrosis, high levels have been found. Sarcoidosis could also feature increased eNO. Low levels have been found in primary ciliary dyskinesia, bronchopulmonary dysplasia, and pulmonary arterial hypertension. In the latter condition, inhaled NO is used as a diagnostic test of the response of the pulmonary arteries to vasodilators (agents that relax the blood vessels).

eNO has also been associated with wheeze, rhinitis and nasal allergy in primary school children. [22]

Exposure to air pollution has been associated with decreased, [23] and increased eNO levels. [24] [25] [26]

Measurement techniques

An experimental setup used to measure the fraction of exhaled nitric oxide (FeNO) in human breath samples. The subject blows into the tube (1) after a mouthpiece (2) has been connected to it. The wires on the side are part of the system that measures parameters like breath velocity, while the exhaled gas is taken to a FeNO analyzer (3). Exhaled NO experiment.jpg
An experimental setup used to measure the fraction of exhaled nitric oxide (FeNO) in human breath samples. The subject blows into the tube (1) after a mouthpiece (2) has been connected to it. The wires on the side are part of the system that measures parameters like breath velocity, while the exhaled gas is taken to a FeNO analyzer (3).

The most widely used technique to measure eNO is with a chemical reaction that produces light; this is called a chemiluminescence reaction. The NO in the breath sample reacts with ozone to form nitrogen dioxide in an excited state. When this returns to its ground state, it emits light in quantities that are proportional to the amount of exhaled NO.

evernoa medical device for measurement of exhaled nitric oxide Evernoa FENO device.jpg
evernoa medical device for measurement of exhaled nitric oxide

The subject can exhale directly into a measurement device ('online' technique), or into a reservoir that can afterwards be connected to the analyser ('offline' technique). [27] With the former technique, the early and later NO in the breath sample can be analysed separately. The test requires little coordination from the subject, and children older than 4 can be tested successfully. [28] [29]

The National Institute of Clinical Excellence (NICE) in the UK have published guidance on available measuring devices: https://www.nice.org.uk/guidance/dg12

Reference range

The upper normal level of eNO in different studies ranges from 20 to 30 parts per billion. However, several major features influence the reference values. Men have higher eNO values than women. Smoking notoriously lowers eNO values, and even former smoking status can influence results. The levels are higher in people with an atopic constitution (a tendency towards allergies). [30] The fraction of eNO is also flow-dependent (higher at lower flow rates and vice versa), so measurements are normally measured at 50 ml/s. Age or height could also considerably confound eNO values in children. [28] The magnitude of these effects lies in the order of 10%, so even single cut-off values might be useful. [17]

History

Until the 1980s, nitric oxide, a product of fossil fuel combustion, was thought only to play a role the detrimental effects of air pollution on the respiratory tract. [17] In 1987, experiments with coronary arteries showed that nitric oxide was the long sought endothelium-derived relaxing factor. After scientists realised that NO played a biological role, its role as a cell signalling molecule and neurotransmitter became clear from abundant studies. [31]

NO was first detected in exhaled breath samples in 1991. [32] In 1992, NO was voted molecule of the year by the scientific journal Science . [33] In 1993, researchers from the Karolinska Institute in Sweden were the first to report increased eNO in asthmatics. [34]

Today, NO is not only used in breath tests but also as a therapeutic agent for conditions such as pulmonary arterial hypertension and possibly for the acute respiratory distress syndrome.

Related Research Articles

<span class="mw-page-title-main">Asthma</span> Long-term inflammatory disease of the airways of the lungs

Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath. These may occur a few times a day or a few times per week. Depending on the person, asthma symptoms may become worse at night or with exercise.

<span class="mw-page-title-main">Cough</span> Sudden expulsion of air from the lungs as a reflex to clear irritants

A cough is a sudden expulsion of air through the large breathing passages which can help clear them of fluids, irritants, foreign particles and microbes. As a protective reflex, coughing can be repetitive with the cough reflex following three phases: an inhalation, a forced exhalation against a closed glottis, and a violent release of air from the lungs following opening of the glottis, usually accompanied by a distinctive sound.

<span class="mw-page-title-main">Sputum</span> Mucus that is coughed up from the lower airways

Sputum is mucus that is coughed up from the lower airways. In medicine, sputum samples are usually used for a naked eye examination, microbiological investigation of respiratory infections and cytological investigations of respiratory systems. It is crucial that the specimen does not include any mucoid material from the nose or oral cavity.

<span class="mw-page-title-main">Exhalation</span> Flow of the respiratory current out of an organism

Exhalation is the flow of the breath out of an organism. In animals, it is the movement of air from the lungs out of the airways, to the external environment during breathing. This happens due to elastic properties of the lungs, as well as the internal intercostal muscles which lower the rib cage and decrease thoracic volume. As the thoracic diaphragm relaxes during exhalation it causes the tissue it has depressed to rise superiorly and put pressure on the lungs to expel the air. During forced exhalation, as when blowing out a candle, expiratory muscles including the abdominal muscles and internal intercostal muscles generate abdominal and thoracic pressure, which forces air out of the lungs.

<span class="mw-page-title-main">Rhinitis</span> Irritation and inflammation of the mucous membrane inside the nose

Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip.

<span class="mw-page-title-main">Spirometry</span> Pulmonary function test

Spirometry is the most common of the pulmonary function tests (PFTs). It measures lung function, specifically the amount (volume) and/or speed (flow) of air that can be inhaled and exhaled. Spirometry is helpful in assessing breathing patterns that identify conditions such as asthma, pulmonary fibrosis, cystic fibrosis, and COPD. It is also helpful as part of a system of health surveillance, in which breathing patterns are measured over time.

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Chlamydia pneumoniae is a species of Chlamydia, an obligate intracellular bacterium that infects humans and is a major cause of pneumonia. It was known as the Taiwan acute respiratory agent (TWAR) from the names of the two original isolates – Taiwan (TW-183) and an acute respiratory isolate designated AR-39. Briefly, it was known as Chlamydophila pneumoniae, and that name is used as an alternate in some sources. In some cases, to avoid confusion, both names are given.

<span class="mw-page-title-main">Bronchoconstriction</span> Constriction of the terminal airways in the lungs

Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath.

Exercise-induced bronchoconstriction (EIB) occurs when the airways narrow as a result of exercise. This condition has been referred to as exercise-induced asthma (EIA); however, this term is no longer preferred. While exercise does not cause asthma, it is frequently an asthma trigger.

Reactive airway disease (RAD) is an informal label that physicians apply to patients with symptoms similar to those of asthma. An exact definition of the condition does not exist. Individuals who are typically labeled as having RAD generally have a history of wheezing, coughing, dyspnea, and production of sputum that may or may not be caused by asthma. Symptoms may also include, but are not limited to, coughing, shortness of breath, excess mucus in the bronchial tube, swollen mucous membrane in the bronchial tube, and/or hypersensitive bronchial tubes. Physicians most commonly label patients with RAD when they are hesitant about formally diagnosing a patient with asthma, which is most prevalent in the pediatric setting. While some physicians may use RAD and asthma synonymously, there is controversy over this usage.

Occupational asthma is new onset asthma or the recurrence of previously quiescent asthma directly caused by exposure to an agent at workplace. It is an occupational lung disease and a type of work-related asthma. Agents that can induce occupational asthma can be grouped into sensitizers and irritants.

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Biological functions of nitric oxide are roles that nitric oxide plays within biology.

<span class="mw-page-title-main">Pathophysiology of asthma</span> Medical condition

Asthma is a common pulmonary condition defined by chronic inflammation of respiratory tubes, tightening of respiratory smooth muscle, and episodes of bronchoconstriction. The Centers for Disease Control and Prevention estimate that 1 in 11 children and 1 in 12 adults have asthma in the United States of America. According to the World Health Organization, asthma affects 235 million people worldwide. There are two major categories of asthma: allergic and non-allergic. The focus of this article will be allergic asthma. In both cases, bronchoconstriction is prominent.

<span class="mw-page-title-main">Eosinophilic bronchitis</span> Medical condition

Eosinophilic bronchitis (EB) is a type of airway inflammation due to excessive mast cell recruitment and activation in the superficial airways as opposed to the smooth muscles of the airways as seen in asthma. It often results in a chronic cough. Lung function tests are usually normal. Inhaled corticosteroids are often an effective treatment.

Exhaled breath condensate (EBC) is the exhalate from breath, that has been condensed, typically via cooling using a collection device. EBC reflects changes in the respiratory fluid that lines the airways and is an inexpensive, non-invasive tool that has potential for scientific research. Despite its promises, it has not been proven for screening or diagnosing diseases of the lung and other conditions, yet. It has long been appreciated that the exhaled breath is saturated by water vapour, but using it for studies of the lung was probably first described in the Russian scientific literature.

Chronic cough is long-term coughing, sometimes defined as more than several weeks or months. Generally a cough lasting for more than eight weeks for an adult would meet the clinical definition of a chronic cough; and for children this threshold is lower. The term can be used to describe the different causes related to coughing, the three main ones being upper airway cough syndrome, asthma and gastroesophageal reflux disease. It occurs in the upper airway of the respiratory system. Generally, a cough lasts around one to two weeks; however, chronic cough can persist for an extended period of time defined as six weeks or longer. People with chronic cough often experience more than one cause present. Due to the nature of the syndrome, the treatments used are similar; however, there are a subsequent number of treatments available, and the clinical management of the patients remains a challenge. Risk factors include exposure to cigarette smoke, and exposure to pollution, especially particulates.

<span class="mw-page-title-main">Asthma trigger</span> Factor that provokes symptoms of asthma

Asthma triggers are factors or stimuli that provoke the exacerbation of asthma symptoms or increase the degree of airflow disruption, which can lead to an asthma attack. An asthma attack is characterized by an obstruction of the airway, hypersecretion of mucus and bronchoconstriction due to the contraction of smooth muscles around the respiratory tract. Its symptoms include a wide range of manifestations such as breathlessness, coughing, a tight chest and wheezing.

Asthma phenotyping and endotyping is a novel approach to asthma classification inspired by precision medicine. It seeks to separate the clinical presentations or clusters of signs and symptoms of asthma, known as asthma phenotypes, from their underlying etiologies or causes, known as asthma endotypes.

References

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