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)]
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(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)
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