The Use of Exhaled Nitric Oxide Measurements In Asthma

Not many of us know that there is a new marker for bronchial asthma - to aid the diagnosis, therapeutic monitoring, control monitoring, etc. This marker has been studied in many trials, but how extensive will this marker be used in clinical practice? Will it be readily available in emergency departments for day to day clinical use in the near future?

The past few decades have seen a paradigm shift in our understanding of the pathogenesis of bronchial asthma.

Rather than seeing bronchial asthma as a bronchoreactive airway disease, it is now seen as a TH-2 mediated inflammatory disease that involves both the large and small airways (Busse & Lemanske, 2001).

In fact, studies done during these last three decades have shown that distal airways inflammation (airways with less than 2 mm diameter) is a prominent feature in this disease (Martin, 2002).

Conventionally, the diagnosis of asthma is based on history, particularly with the presence of a triad of wheeze, shortness of breath and cough (GINA Guidelines, 2008) [Click here to download a free copy of Global Initiative For Asthma]. Unfortunately such manifestations are variable.

For example, the use of serial peak expiratory flow rate or spirometry measurements as well as demonstrating airway reversibility with an increase of FEV1 of at least 12% from baseline 15 minutes post bronchodilator inhalation (GINA Guidelines, 2008); but such tests are based on demonstrating abnormal airway physiology and may often not be present in mild asthma (Smith et al, 2004). [Excellent article. Click here to download full text in pdf]

Other surrogate or direct markers such as methacholine or adenosine monophosphate challenge tests, as well as fiberoptic bronchoscopy utilizing bronchoalveolar lavage, are time consuming, invasive and uncomfortable for the patients.

Two recently proven methods to guide adjustment of asthma management are fraction of exhaled nitric oxide (FENO) and inducing sputum for eosinophilia.

Being a relatively new marker for asthma, NO was first described in the 1980s (Zeidler et al, 2004). It was initially known as endothelial derived relaxation factor (EDRF), as it was shown to be responsible for vasodilatation of arterioles (Furchgott & Zawadzki, 1980). Subsequent researches also show that nitric oxide (NO) plays a role in inflammation, immunity and neurotransmission (Zeidler et al, 2004).

NO is produced from the conversion of L-arginine to NO and citrulline by Nitric oxide synthase (NOS). Constitutive expression of NOS produces low level of NO in healthy lungs. Inducible nitric oxide synthase on the other hand, is responsible for the increased levels of NO produced in inflammatory states in the lung and is markedly upregulated by interferon-γ, tumor-necrosis factor-α, and interleukin-1β and downregulated by corticosteroids (Robbins et al, 2004).

FENO has been shown to be increased in proportion to the severity of bronchial wall inflammation (Payne et al, 2001), severity of airway hyperresponsiveness (Jones et al, 2001; Jatakanon et al, 1998) and its level has been shown to be reduced in a dose dependent manner (Kharitonov et al, 2002; Jones et al, 2002). Unlike induced-sputum analysis, FENO measurements are easy to perform, reproducible, and was highly accepted by patients (Kharitonov et al, 2003).

As mentioned, conventional tests, as mentioned above, are primarily based on demonstrating abnormal airway physiology, such as bronchial hyperresponsiveness. Therefore, these tests are not sensitive enough particularly in cases of mild asthma.

Unfortunately, although conventional tests may show normal results in such cases, it has been shown that, even in asymptomatic asthmatic patients with remission of symptoms of up to one year have been shown to have continued eosinophilic inflammation and bronchial hyperresponsiveness (van den Toorn et al, 2000; van den Toorn et al, 2001; Spallarossa et al, 2003). In such cases, FENO is particularly helpful, because it has high discirminatory power (Dupont et al, 2003; Malmberg et al, 2003; Deykin et al, 2002).

As mentioned, these conventional tests are also time consuming, and may require repeated measurements (for example, in cases of serial peak flow measurements). This may also affect patients' compliance (Smith et al, 2008). [Excellent article, click here to download the full text from New England Journal of Medicine (NEJM)]


References:
Busse WW, Lemanske RF, Jr. Asthma. N Engl J Med 2001; 344 (5):350-62.

Deykin A, Massaro AF, Drazen JM et al. Exhaled nitric oxide as a diagnostic test for asthma: online versus offline techniques and effect of flow rate. Am J Respir Crit Care Med 2002; 165 (12):1597-601.

Dupont LJ, Demedts MG, Verleden GM. Prospective evaluation of the validity of exhaled nitric oxide for the diagnosis of asthma. Chest 2003; 123 (3):751-6.

Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288 (5789):373-6.

Jatakanon A, Lim S, Kharitonov SA et al. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax 1998; 53 (2):91-5.

Jones SL, Kittelson J, Cowan JO et al. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001; 164 (5):738-43.

Kharitonov SA, Gonio F, Kelly C et al. Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children. Eur Respir J 2003; 21 (3):433-8.

Malmberg LP, Pelkonen AS, Haahtela T et al. Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma. Thorax 2003; 58 (6):494-9.

Martin RJ. Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin Immunol 2002; 109 (2 Suppl):S447-60.

Payne DN, Adcock IM, Wilson NM et al. Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma, after treatment with oral prednisolone. Am J Respir Crit Care Med 2001; 164 (8 Pt 1):1376-81.

Robbins RA, Barnes PJ, Springall DR, et al.: Expression of inducible nitric oxide in human lung epithelial cells. Biochem Biophys Res Commun 1994, 203:209-218.

Smith AD, Cowan JO, Filsell S et al. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med 2004; 169 (4):473-8.
(Click here to download)

Smith AD, Cowan JO, Brassett KP et al. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005; 352 (21):2163-73. (Click here to download)

Spallarossa D, Battistini E, Silvestri M et al. Steroid-naive adolescents with mild intermittent allergic asthma have airway hyperresponsiveness and elevated exhaled nitric oxide levels. J Asthma 2003; 40 (3):301-10.

van den Toorn LM, Overbeek SE, de Jongste JC et al. Airway inflammation is present during clinical remission of atopic asthma. Am J Respir Crit Care Med 2001; 164 (11):2107-13.

van den Toorn LM, Prins JB, Overbeek SE et al. Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000; 162 (3 Pt 1):953-7.

Zeidler MR, Kleerup EC, Tashkin DP. Exhaled nitric oxide in the assessment of asthma. Curr Opin Pulm Med 2004; 10 (1):31-6.