Key points

FeNO: Why should I care?

Short answer: It may help manage your asthmatic patients.

The challenges of asthma care include : Does this patient have asthma ( Figs. 1 and 2 )? How severe is the asthma? What medications will help this patient most? Is this patient improving or getting worse? Is this patient compliant with his/her medications? Is this patient at current risk for an asthma exacerbation?

Front view of the NIOX MINO with its touchscreen showing the cloud graphic.

Back view of the NIOX MINO. The opening toward the top is where the disposable mouthpiece is inserted. Because the patient blows from the back and the graphic is on the front, it is easiest the have the patient watch the touchscreen in a mirror. There is also an audio cue, with a steady sound for acceptable inhalation speed and a high-pitched beeping when the speed is too slow or too fast.

Traditional methods for answering these questions include symptom questionnaires, peak flow measurements, spirometry, eosinophil count in induced sputum, bronchoalveolar lavage (BAL) fluid or biopsy, and spirometric methacholine challenge. The problems with these methods are subjectivity (questionnaire), dependence on patient voluntary performance (peak flow, spirometry, and methacholine challenge), invasiveness (induced sputum, BAL, and biopsy), and time and complexity of performing them (all except questionnaires and peak flow). There is, therefore, a continual search for quick and easy objective measurements to help with asthma diagnosis and management.

FeNO: Why should I care?

Short answer: It may help manage your asthmatic patients.

The challenges of asthma care include : Does this patient have asthma ( Figs. 1 and 2 )? How severe is the asthma? What medications will help this patient most? Is this patient improving or getting worse? Is this patient compliant with his/her medications? Is this patient at current risk for an asthma exacerbation?

Front view of the NIOX MINO with its touchscreen showing the cloud graphic.

Back view of the NIOX MINO. The opening toward the top is where the disposable mouthpiece is inserted. Because the patient blows from the back and the graphic is on the front, it is easiest the have the patient watch the touchscreen in a mirror. There is also an audio cue, with a steady sound for acceptable inhalation speed and a high-pitched beeping when the speed is too slow or too fast.

Traditional methods for answering these questions include symptom questionnaires, peak flow measurements, spirometry, eosinophil count in induced sputum, bronchoalveolar lavage (BAL) fluid or biopsy, and spirometric methacholine challenge. The problems with these methods are subjectivity (questionnaire), dependence on patient voluntary performance (peak flow, spirometry, and methacholine challenge), invasiveness (induced sputum, BAL, and biopsy), and time and complexity of performing them (all except questionnaires and peak flow). There is, therefore, a continual search for quick and easy objective measurements to help with asthma diagnosis and management.

What is FeNO?

Short answer: FeNO is a marker for eosinophilic inflammation in the lungs.

FeNO a marker for inflammation that can be measured in the exhaled breath. Human airways respond to inflammation by producing nitric oxide (NO) via nitric oxide synthase (NOS). NOS2A isoform is produced by cells in the bronchial wall, and this mechanism overproduces NO when there is eosinophilic inflammation. It is being investigated as an objective measure to assist with asthma management.

The first machines for measuring exhaled NO depended on chemiluminescence analyzers and were fairly large and nonportable. Currently, most clinical offices in the United States use the NIOX MINO (Aerocrine AB), which measures FeNO by an electrochemical analyzer. The handheld machine has a disposable mouthpiece that is changed between patients. Because concentration of NO depends on the speed of exhalation, the NIOX MINO is calibrated to a preferred flow rate of 50 mL/s. It has a sensitivity and reproducibility of 1 ppb, with a range of 1 ppb to 500 ppb. Patients are instructed to exhale deeply, place their mouth on the mouthpiece, and inhale deeply through the mouthpiece. This inhalation through the built-in filter screens out NO in the inhaled breath. Immediately after inhalation, patients exhale at a slow, steady rate, holding near 50 mL/s for 10 seconds. There is a floating cloud on the machine that provides video game–like instant feedback to patients. Additionally, an on-computer module add-on is available that is even more engaging, featuring a hot-air balloon flying over water between two land masses.

FeNO measurement is noninvasive, easy, and simple to perform. Most patients, including young children, are able to perform it correctly with a bit of coaching (much less extensive than that required for reliable spirometry). The exhalation needed for FeNO is gentle, like blowing on soup to cool it, rather than the prolonged forceful exhalation required for spirometry, so it is easier for the elderly and the ill. The equipment is inexpensive and easy to maintain.

Asthmatic patients not on inhaled corticosteroids (ICSs) often have elevated FeNO readings. The manufacturer of the NIOX MINO recommends that values under 25 (20 for children) be regarded as normal, those between 25 and 50 (20–40 for children) as intermediate, and values over 50 (40 for children) as abnormally high.

Some of the initial enthusiasm about the potential usefulness of FeNO in diagnosing and managing asthma has been tempered as reports accrue identifying other pathologies also affecting FeNO. The remainder of this article summarizes current findings and thoughts about how and when FeNO can be useful in the management of asthma.

What else affects FeNO measurement?

Short answer: FeNO is affected by multiple demographic and lifestyle issues.

FeNO is affected by genetic phenotypes, age and gender, race, possibly height and weight, and definitely the presence of atopic disease or current upper respiratory tract infection. FeNO is higher in males than females and higher in adults than children. It is higher in Chinese schoolchildren and African American adults than in white populations of similar ages.

Vigorous exercise prior to FeNO measurement can produce falsely low levels.

Spirometry before FeNO may or may not have a similar effect. Breath-holding increases FeNO. Depression and prolonged stress can lower FeNO levels. Acute exposure to moderate altitude significantly increased FeNO by approximately 20%. Increased air pollution is associated with higher FeNO. Specifically, diesel exhaust increases FeNO in a laboratory setting, but ozone does not. Allergy immunotherapy decreases FeNO.

It is recommended that patients do not eat or drink for an hour before testing. Specifically, alcohol, like smoking, decreases FeNO, and nitrate-containing foods, such as bacon or lettuce, transiently increase FeNO.

Sordillo and colleagues studied children, finding that allergy to indoor antigens was associated with increased FeNO. Additionally, watching more than 10 hours of television during the weekdays of each week was associated with increased FeNO even after controlling for indoor allergen exposure, allergic sensitization, and body mass index. They concluded that sedentary behavior might be another independent factor capable of increasing FeNO.

What other diseases affect FeNO?

Short answer: FeNO is affected by several other pulmonary pathologies as well as some nonpulmonary ones.

FeNO is abnormally low in pulmonary hypertension, cystic fibrosis, HIV infection, and primary ciliary dyskinesia. It is relatively low in stable bronchiectasis. FeNO has been found significantly elevated in patients with acute eosinophilic pneumonia.

Obstructive sleep apnea is associated with higher oral NO and FeNO levels. These tend to decrease after appropriate continuous positive airway pressure treatment.

How good is FeNO as a screen for asthma?

Short answer: There is contradictory evidence, with some studies showing excellent correlation, and others showing no correlation. Overall consensus seems that FeNO may be useful screening for asthma in patients with allergic rhinitis (AR) and/or respiratory symptoms .

Investigations of rhinitis patients and population-based studies have demonstrated that many people have subclinical bronchial hyperreactivity (BHR). BHR is associated with future development of AR and asthma. If there were a way to identify not only patients with undiagnosed or undertreated frank asthma but also those with subclinical lower airway inflammation who are at risk of developing reactive airway disease or asthma, these patients could be targeted with more-aggressive treatment.

Lee and colleagues investigated using FeNO to screen for asthma in Chinese schoolchildren. They measured FeNO in controls and in children with physician-diagnosed AR and/or asthma and/or atopic dermatitis. They showed that asthma and AR were independently associated with increases in FeNO, concluding that “other diseases besides asthma should be considered when applying FeNO as a screening tool for asthma…” It may be accurate to draw another conclusion from their data: that FeNO screening of patients with AR and no history of asthma can identify those who should have further work-up for asthma.

Ciprandi and colleagues found that children with AR or asthma who had FeNO greater than 34 ppb were more likely to have reversibility after bronchodilator administration, especially if they were also sensitized to perennial allergens. This suggests that both FeNO and pattern of allergen exposure can help guide identification of children who would benefit from further pulmonary work-up.

Schleich and colleagues examined how well FeNO or forced expiratory volume in the first second of expiration (FEV ₁ ) less than 101% predicted a positive outcome to a methacholine challenge in steroid-naive patients with respiratory symptoms. Inhaled methacholine stimulates bronchoconstriction, with a decrease of 20% or more generally regarded as indicating asthma. They found that a FeNO greater than 34 ppb had a positive predictive value of 88%, specificity of 95%, sensitivity of 35%, and negative predictive value of 662% with respect to a positive methacholine challenge. Because methacholine challenge is a time-consuming complex test compared with FeNO, there may be a role for FeNO in screening for early asymptomatic BHR, permitting closer follow-up of those who are at higher risk for developing respiratory disease.

Ciebiada and colleagues also looked at patients with seasonal AR (SAR) and no asthma, comparing them with normal controls. All had FeNO, nasal congestion scores, and nasal peak inspiratory flow measured 6 weeks before pollen season, at the height of pollen season, and 6 weeks after pollen season. SAR patients had higher FeNO preseason, and FeNO increased in both groups in pollen season, but was a significant increase only in the SAR group. This confirms that exposure to allergens tends to increase FeNO.

Fukuhara and colleagues screened patients presenting with cough, wheeze, or dyspnea. When traditional screening methods for asthma were compared with FeNO, a FeNO greater than 40 had 78.6% sensitivity and 89.5% specificity for identifying asthma. These investigators mention the necessity of excluding other pulmonary pathologies but concluded that FeNO screen for asthma was effective in such a population for screening in daily clinical practice.

Kakoaklioglu and colleagues screened FeNO levels in 5 groups: controls without rhinitis and patients with non-AR (NAR) and AR, with or without asthma. FeNO was, as expected, lowest in controls and NAR without asthma. The FeNO levels in AR patients with or without asthma were, as expected, higher than in NAR patients without asthma or the controls. But the highest levels occurred in asthmatic patients with rhinitis, whether AR or NAR. These investigators concluded that whether a patient has rhinitis or not was a stronger influence on increasing FeNO that whether the rhinitis is allergic in nature or not.

ElHalawani and colleagues studied patients without a history of asthma, atopy, or smoking referred for evaluation of possible exercise-induced bronchospasm (EIB), which used to be called exercise-induced asthma. Sometimes presumed EIB is treated empirically with a pre-exercise inhaled bronchodilator; when, however, the precise cause of exertional dyspnea is unclear, spirometry measurement before and after 6 to 8 minutes of treadmill or similar exercise is required. This group’s focus was whether FeNO (faster, easier, and less expensive) could obviate some of this exercise testing. They measured FeNO before exercise and every 5 minutes for 30 minutes of exercise. They found that no patients with an initial FeNO of less than 12 ppb had EIB demonstrated by this spirometry. Specifically, in terms of effectiveness in excluding EIB, a FeNO less than 12 had a sensitivity of 1.0, a specificity of 0.31, a negative predictive value of 0.19, and a positive predictive value of 1.0. This finding suggests that patients presenting with exertional dyspnea and a FeNO less than 12 ppb can be spared exercise spirometry, with attention directed to other possible causes of this dyspnea.

Buchwald and colleagues used a similar strategy in screening asthmatic children for EIB. Their group found that children with a FeNO less than 20 (or less than 12 if they were currently on ICSs) had only 1 chance in 10 of having concurrent EIB. They conclude, “Measurement of FeNO is a simple, and time- and resource-efficient tool that may be used to screen for EIB testing and therefore optimizes the resources for exercise testing in pediatric asthma monitoring.”

A study of Mexican children with persistent asthma showed that a FeNO over 20 was associated with poorer asthma control and lung function. Such screening could provide an opportunity for intensified environmental and pharmaceutical intervention to prevent future exacerbations.

In a primary care setting, in a group of children with AR and with or without asthma, FeNO was associated with house dust mite sensitization but not with nasal or asthma symptoms or rhinitis-related quality of life.

My take from these studies is that FeNO provides useful screening for patients with AR and that levels over approximately 40 ppb, probably over 35 ppb in children, should prompt a further look at the possibility of BHR or asthma.