© 2003 American Thoracic Society
The Blood Lung Function TestDoes It Exist for Asthma?Allergy and Inflammation Sciences University of Southampton Southampton, United Kingdom Over the last decade, there has been a vast research enterprise to identify circulating markers of asthma. The aim of such studies has been to predict the onset of asthma, aid diagnosis when this is in doubt, predict response to treatment, and monitor the progression of disease and severity. Given the polygenic nature of asthma and the multitude of environmental factors that affect outcomes, this enterprise seems predictably doomed to failure. This, however, has not deterred investigators, including myself (1). The article by La Grutta and colleagues in this issue of AJRCCM (pp. 1490–1495) has pursued the hypothesis that function of peripheral blood mononuclear cells will reflect and predict asthma severity in children (2). This makes the assumption that there is a systemic component to asthma. There are three possible interpretations of any study that has identified a virtual blood test of lung function. Asthma is a systemic disease, and circulating markers are directly representative of the airway abnormality; abnormalities in the airways will produce an overflow effect that can be detected in the circulation, and cellular malfunction in the airway is mirrored by similar cellular abnormalities in the circulation. Perhaps the latter interpretation is the most likely in relationship to the observations of La Grutta and coworkers (2). At present, only relatively invasive investigations employing bronchoscopy, bronchoalveolar lavage, and bronchial biopsy are truly able to provide valid information on the degree of chronic inflammation within the airway (3–5). Uncertainty about the prognosis of wheezing illness in early childhood makes decisions about employing a rational program of therapy difficult. Some authors encourage the early and aggressive use of antiinflammatory therapy, primarily with inhaled corticosteroids. Other authors point to a lack of evidence of airway inflammation and remodeling in young children and suggest a rather more circumspect approach (6). As emphasized by La Grutta and colleagues, the inflammatory changes that occur in the airways of children developing asthma are likely to evolve at a very early stage. Indeed, the clinical presentation of asthma symptoms is the tip of the iceberg of an entire range of subclinical pathophysiologic events. Under such circumstances, the identification of noninvasive or minimally invasive biomarkers of disease activity is essential. Hitherto all studies, including that by La Grutta and coworkers (2), have concentrated on biomarkers that reflect airway inflammation. It is very important to note, however, that in the subgroup of patients with difficult asthma, a key component of the pathology is remodeling with thickening of the reticular basement membrane (7). The aim for the future must, therefore, be to find markers that represent this component of the pathology as well. Indeed, we have found that thickening of the reticular basement membrane actually predicts ongoing asthma in young children when they first present with minor respiratory symptoms (8).
La Grutta and coworkers (2) studied a small group of 29 children with asthma, representing two extremes of the disease: 12 patients had intermittent symptoms, apparently only requiring treatment with short-acting ß-agonists, as compared with 17 children classified as having moderate persistent disease. The latter group received high doses of inhaled corticosteroid, which inevitably has some systemic effect, and also continuous long-acting ß-agonists; as such, the patients would be considered to meet Step 3/4 in the Global Initiative for Asthma guidelines (9). The compliance in the latter children was substantiated by demonstrating a significantly reduced basal morning plasma cortisol concentration. Perhaps rather surprisingly, the children with intermittent asthma had significantly lower morning cortisols than their age-matched control subjects. Does this mean that asthma itself affects cortisol (which has not been shown in previous studies) or, more likely, that these children were using steroids unbeknown to the investigators? The study focused on the spontaneous release of cytokines in cultures of peripheral blood mononuclear cells, and the levels of p65 and phosphorylated inhibitory protein of nuclear factor In many respects, the study of La Grutta and coworkers (2) is very similar to that of Payne and colleagues (10), which suggested there were subgroups of subjects with difficult asthma, with ongoing steroid insensitive airway inflammation, as exemplified by a lack of fall in levels of exhaled nitric oxide after a course of oral prednisolone (10). Several studies have suggested a relationship between exhaled nitric oxide and evidence of eosinophilic mucosal inflammation (11, 12). This suggests that in terms of monitoring airway inflammation, perhaps the most appropriate noninvasive marker is exhaled nitric oxide rather than the labor-intensive and expensive measurement of circulating markers. In patients already established on high-dose inhaled steroid therapy, other than in those with significant steroid insensitivity, exhaled nitric oxide will not on the basis of the study by La Grutta and coworkers discriminate the subjects with persistent asthma; in this situation, measurement of activity of peripheral blood mononuclear cells may have utility. None of these approaches, however, will provide any indication of the degree of airway remodeling. Whether there will ever be a marker of this component of the pathophysiology of asthma remains to be identified. Currently, the answer to the question is "no." A blood biomarker of lung function in asthma does not exist, and infinitely more research is required to elaborate on which components of this disease are susceptible to monitoring noninvasively. REFERENCES
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