EDITORIAL
WHY SHOULD EXHALED NITRIC OXIDE BE EVALUATED?
In recent years a number of studies have been published about the interest of evaluating exhaled nitric oxide (ENO) in asthmatic patients (1). This compound, derived from L-arginine by the action of nitric oxide synthetase (NOS) in the presence of oxygen, has been shown is significantly higher in patients with asthma than in normal subjects, so it could be a marker of bronchial inflammation (2, 3). Based on this simple premise, it would be interesting to be able to evaluate ENO to confirm the diagnosis of the disease in dubious cases. However, things are more complicated than that because this NO is present in bronchial inflammation as a result of the intervention of different cytokines and derives from the action of a constitutive synthetase (cNO), in contrast with catalyzed, induced NO production (iNO) resulting from bacterial and viral infections, including rhinovirus (4), which also are responsible for some asthma attacks. Consequently, localized infections of the bronchial tract and upper airways, particularly the paranasal sinuses, also increase NO in exhaled air. This should be taken into consideration when evaluating NO for the diagnosis of asthma. Even in the absence of infection, the NO content of the paranasal sinuses and nasal cavities is physiologically higher than in the bronchial tree (5).
The significance of NO in the pulmonary form of cystic fibrosis (mucoviscidosis) is uncertain (6), although NO may be high in exhaled aire (2). There are also discrepant findings in relation to another important lung disease, COPD. Some authors report high NO levels in exhaled air (7, 8), but in the severe stable form of the disease lower NO levels have been observed (9). Even, the bronchodilator effect of NO has been found to be beneficial in the treatment of this disease (10).
To these possible sources of confusion for the use of ENO evaluations to confirm the presence of asthma must be added other appreciable causes of error that derive from the technique itself and other circumstances. For instance, the ingestion of food rich in nitrites or nitrates, such as lettuce, alcoholic beverages, and even water can affect results, as can L-arginine ingestion. Previous spirometry reduces NO values and salbutamol inhalation increases them (11), as does contaminant NO in environmental air. The exhalatory technique has some difficulties, but no greater than those of any other respiratory function study. These difficulties may be somewhat more difficult to overcome in children.
As a result of these potential sources of alterations in the results, there have been discrepancies in the results of published studies, which have not always considered these factors in ENO assessment. Therefore, different guidelines have been published recently that establish the most recommended standards for performing the technique and interpreting the results of ENO study in adults and children (12, 13). In all likelihood, compliance with these recommendations will help to normalize the technique and, consequently, produce results that can be compared between studies. However, these guidelines provide no normal reference values obtained while following these standards, which would be valuable information in view of the discrepancies found in the literature. It would be particularly interesting to have reference figures for children because it is known that ENO values vary with age.
Aside from these problems, doubt persists as to the usefulness of ENO evaluation in asthmatics or possible asthmatics. It would be helpful if this parameter could be used to differentiate between extrinsic and intrinsic asthma, AAS asthma, occupational asthma, or asthma produced only by exercise. It also would help if it could be used to evaluate severity, which would provide information of prognostic value. However, in the course of asthma attacks, ENO levels similar to those found in stable asthma have been found, so this parameter does not seem to be useful for evaluating the intensity of inflammation (14, 15).
In contrast, it has been shown that ENO can be reduced by some medications, such as inhaled or oral corticoids. This seems to have been demonstrated with the leukotriene antagonists, montelukast (16) and possibly pranlukast (17), as well as after taking environmental measures to reduce the accumulation of dust mites (18). In view of these findings, ENO evaluation is likely to be useful for confirming the effectiveness of medication and the need for modifying therapy.
To summarize, there seems to be no doubt that increased ENO is a good indicator of mucous membrane inflammation of the respiratory tree. However, more experience is needed to determine the precise indications for this determination in daily practice. It is hoped that it may provide more information than other non-invasive methods that at first seemed promising (19), but finally did not meet this need.
It also would be useful to have a system for evaluating the appropriate ENO in small children (13). In this case, this parameter might serve to distinguish between asthma and wheezing bronchitis or other obstructive bronchial diseases in small children.
F. Muñoz-López
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