Inflammatory Markers in Clinical Practice

NICOLA WILSON and SOREN PEDERSEN

Department of Paediatrics, Royal Brompton Hospital, London, United Kingdom; and Department of Paediatrics, Kolding Hospital, Kolding, Denmark

	INTRODUCTION

TOP INTRODUCTION WHAT DO WE KNOW? WHAT DO WE NEED... HOW CAN WE ACHIEVE... REFERENCES

Currently, the noninvasive clinical assessment of airway inflammation in young children is limited. The detection of raised blood eosinophil levels or evidence of eosinophil activation proteins in blood or urine, such as eosinophil cationic protein (ECP) or eosinophil protein X (EPX), can be used in addition to the examination of nasopharyngeal secretions. In the near future it is likely that tidal breathing methods for measuring exhaled nitric oxide (NO) and other gases will be validated for use in the younger child. The analysis of other constituents of breath, such as exhaled proteins, that are currently being investigated as potential indicators of airway pathology (1), is also likely to be feasible in this age group in due course. This may broaden the application of assessment of airway inflammation to conditions other than those associated with eosinophilia. However, few studies have been performed in young children. For the purposes of this review, we have therefore extrapolated findings from the older age group by assuming that the issues are likely to be similar, that is, if airway inflammation can be appropriately monitored noninvasively in this age group.

In clinical practice we deal with individuals. Extrapolating evidence gathered from mechanistic or diagnostic studies of inflammatory markers to the clinical management of individual patients is questionable for patients of all ages. To do so effectively, the sensitivity and specificity of each test as applied to the required outcome, determined in a relevant population, are needed. Furthermore, it should be ascertained that the test contributes additionally to the information obtained from a simple clinical history.

	WHAT DO WE KNOW?

TOP INTRODUCTION WHAT DO WE KNOW? WHAT DO WE NEED... HOW CAN WE ACHIEVE... REFERENCES

Diagnosis

Asthma. While it is accepted that asthma is an inflammatory disease of the airways, no current marker of inflammation is both highly sensitive and specific in its diagnosis. Significant differences are found between patients and healthy controls, but the overlap is too great for use with confidence in individual patients (2). The degree of overlap (hence sensitivity and specificity) depends, to some extent, on the choice of the groups under comparison. For example, a diagnostic sensitivity and specificity for serum ECP > 16 µg/L of only 54 and 74%, respectively, has been reported when comparing children with currently symptomatic asthma versus nonatopic control subjects (3). If these tests had been applied to a population of young children, an age group in which the diagnostic "gray" area is most marked, the distinction between groups is likely to be even more blurred. Circulating markers of eosinophil activation reflect atopy, not asthma (4). Furthermore, evidence of airway eosinophil activation is found in a number of other conditions of lower airway inflammation (see below). This raises the question as to which population a diagnostic marker utility should be judged against. For use in clinical practice, perhaps the comparison should be made with those with respiratory symptoms, both atopic and nonatopic.

For the past decade, airway eosinophilia has been considered to be the defining feature of asthma (as was increased bronchial responsiveness in the past). However, eosinophils are found in the airways of some subjects without clinical asthma and are not found in others considered to have asthma on clinical grounds (7, 8). While there is ample evidence to link airway inflammation with asthma and antiinflammatory treatment with improvement in both symptoms and evidence of airway inflammation, the concept that "asthma is inflammation" may turn out to be as simplistic as the notion that "asthma is bronchial hyperresponsiveness." If, as seems likely, asthma is a clinically indefinable syndrome consisting of a number of overlapping dimensions or superimposed risk factors (9, 10), then concentrating on only one aspect will not encompass the whole story.

Other conditions. In contrast to the diagnostic use of exhaled NO in asthma, the measurement of nasal NO had both a 95% positive and 95% negative predictive value in the diagnosis of primary ciliary dyskinesia (PCD) (11). Compared with healthy children, both lower airway and nasal NO were significantly reduced in those with PCD but only nasal NO distinguished between the two groups. The reason for this is not clear, although the barrier effect of mucus is one possible explanation. Measurement of nasal NO may therefore provide a simple, noninvasive initial screening test for PCD.

Exhaled NO is raised in noncystic fibrosis bronchiectasis in adults (12), but the test has no diagnostic role (N. Wilson, unpublished observations, 1999).

Prediction in Infancy of Later Respiratory Disorders

Development of asthma. The search continues to find a test that can identify infants that are at future risk of developing asthma. Currently, no test appears to be an improvement on family history (13). Certain risk factors indicating atopy, or an increased risk of developing atopy (such as a family history), are increased in babies who have already wheezed (14, 15). Two studies have suggested that mean serum ECP levels are increased in wheezy infants in whom symptoms persist (16, 17). However, two other studies did not find either circulating eosinophils or ECP levels to be predictive of later asthma in babies assessed at their first episode of bronchiolitis (18, 19). These studies included small numbers of patients. If subsequent studies show that large numbers of patients are needed for prediction then the test will not be sensitive on an individual patient basis.

Development of chronic lung disease of prematurity. Evidence of pulmonary inflammation in tracheal aspirates and lavage fluid has been found in premature infants recovering from respiratory distress syndrome (20). Levels of intercellular adhesion molecule 1 and ECP were raised, while levels of transforming growth factor  were reduced, in those who later developed chronic lung disease of prematurity (CLD). Further studies are needed to determine the use of these markers as prognostic indicators.

Monitoring Inflammation in Asthma

Current symptoms. In a condition such as asthma, in which treatment is directed at abolishing the underlying inflammation, it is logical to assess the response of the target organ. To optimize treatment, measurement of circulating and urinary eosinophil proteins, as well as exhaled NO, has been recommended for this purpose on the basis of correlation with broad measures of severity in cross-sectional studies (23, 24). However, findings in studies have been conflicting, or the relationship between severity and marker was weak (2). Indeed, many workers have not found a relationship between inflammatory markers and current symptom severity in treated asthma (25, 26) (Figure 1). When these markers were monitored before and after institution of antiinflammatory therapy, significant mean decreases were seen in some (27), but not all (25), studies. A further problem is that children with current asthma symptoms are not infrequently seen without any evidence of airway inflammation. Airway biopsy evidence in children who have severe asthma despite receiving high doses of inhaled corticosteroids is beginning to confirm the lack of eosinophilic inflammation in some individuals (D. Payne, personal communication, 1999). This suggests that continuing symptoms may be related to some other process, in which the role of antiinflammatory treatment is not clear.

View larger version (21K): [in this window] [in a new window]   Figure 1.   Relationship between exhaled nitric oxide and serum eosinophil cationic protein (ECP) levels and asthma severity in 34 children, as determined by (a) inhaled daily steroid dose and (b) symptoms in the past month while attending a hospital asthma clinic (N. Wilson, unpublished observations, 1999).

Confounding effect of poor treatment compliance. Evidence of airway inflammation, for example, a raised exhaled NO, in a symptomatic older child may well be indicative of failure to take medication. Uncertainty about treatment compliance in patients taking part in clinical studies is a major problem when the relationship between antiinflammatory agent, inflammatory marker, and symptom severity is being sought. This is likely to be a particular problem when the long-term outcome in relatively mild cases, or in the very young, is being assessed. There is currently no optimal solution to the problem of assessing treatment compliance.

Predictive value. Measurement of inflammatory markers could be of clinical value in tailoring therapy if they predict future progress. Two studies have considered this, using serum levels of ECP and eosinophil-derived neurotoxin (EDN). Fujisawa and colleagues assessed symptoms for 3-4 wk before and after ECP measurement in a cross-sectional study of 28 children with asthma (23). Although there were some differences in ECP levels between those with and without symptoms, the relationship to future prognosis was not definitive and ECP levels were not clearly predictive of symptoms. No predictive value of either ECP or EDN for symptoms was found in a 6-mo longitudinal study in children (30). At present, there are no reports on the value of exhaled NO in terms of predicting future symptoms.

Monitoring Inflammation in Other Conditions

Serum and sputum ECP levels are elevated in a number inflammatory conditions of the lower airways, including mycoplasma pneumonia, viral infections, unexplained cough, and host defense deficiencies (31). In cystic fibrosis, serum ECP levels correlate with lung function (35). However, it is not yet known whether measurement of any inflammatory marker has clinical use either in determining severity or as a guide to antiinflammatory therapy.

Therapeutic Outcomes in Asthma

It is not at all clear which outcome measure (inflammatory marker, lung function, or symptoms) should be used to tailor antiinflammatory therapy. The difficulty arises because these outcome measures do not always correlate (36).

After institution of corticosteroid therapy, different markers of asthma severity respond to different degrees and over different time spans (37, 38). The possibility of excessive treatment also must be added to the equation of optimal management, because of the adverse effects of corticosteroid therapy.

Symptomatic asthma. Broadly speaking, there are two goals of asthma management in which the place of measurement of airway inflammation has not yet been established:

1. Short-term goal. An excellent quality of life without physical or psychological handicap. It is possible to assess (if not to achieve) this goal, although it is not known whether short-term control is improved by monitoring and treating evidence of airway inflammation. Several studies have shown that the addition of a long-acting bronchodilator provides better symptomatic control than doubling the dosage of inhaled corticosteroid (39, 40). Whether this is the case only when there is no evidence of persistent airway inflammation, or whether the added benefit occurs only in the short term, is not known. Further studies are needed, in which an assessment of airway inflammation is made, to elucidate the role of long-acting bronchodilators and asthma symptoms in relation to both short- and long-term prognosis.

2. Long-term goal. A benign prognosis without any ill effect on airway structure of function. A report of a 6-mo randomized controlled trial (in adults) showed a significant improvement in exacerbation rate and forced expiratory volume in 1 s (FEV₁), as well as a difference in the subepithelial reticular layer, when asthma was treated according to airway hyperresponsiveness (a surrogate marker of inflammation) rather than by symptoms and lung function (41). The symptomatic improvement was associated with reduction in the type of airway pathology associated with airway remodeling. The results of this study should encourage a positive attitude toward vigorous treatment of evidence of inflammation and the use of an inflammatory marker to guide management in those with symptomatic asthma. It is not known whether it is valid to extrapolate from studies of adults with long-standing moderately severe asthma to children known to have a fluctuating course.

	WHAT DO WE NEED TO KNOW?

TOP INTRODUCTION WHAT DO WE KNOW? WHAT DO WE NEED... HOW CAN WE ACHIEVE... REFERENCES

Short-Term Outcome

1. Is the pattern of inflammation similar in viral exacerbations of atopic asthma and during simple episodes of viral wheeze?

2. Does treatment of evidence of inflammation reduce exacerbation rate?

Asymptomatic Asthma or Asymptomatic Airway Inflammation

A number of issues remain to be resolved:

1. Should patients with mild or intermittently symptomatic asthma, not receiving antiinflammatory agents, in whom evidence of inflammation is found, be treated?

2. Should patients with well-controlled symptoms be monitored and treated if inflammation is detected (42)? Would this approach improve long-term prognosis?

3. In asymptomatic children with raised NO, is NO playing a protective or pathogenic role?

4. Should those with evidence of airway inflammation but without asthma symptoms, such as patients with hay fever, be treated to prevent future asthma?

Treatment of Inflammation and Long-term Prognosis

1. Is it possible to prevent airway remodeling by vigorously treating all evidence of inflammation?

2. Is there a marker that reflects airway remodeling?

3. Is it necessary to abolish all evidence of inflammation to avoid airway remodeling?

4. Is a thickened basement membrane in young children with asthma always associated with long-term airway dysfunction, or is it a part of the repair process not necessarily associated with poor prognosis?

5. Does the presence of airway inflammation in childhood always indicate a poor prognosis? Many children with asthma, even that associated with atopy, improve during childhood (43). Those that subsequently deteriorate may have a particular reason, such as smoking, pet exposure, or a severe viral infection. Only 2% of children wheezing by 7 yr of age continued to do so throughout childhood (43). What remains to be established is whether airway inflammation fluctuates according to age, depending on environmental factors. If so, would treating an "inflammatory" phase modify future responses?

	HOW CAN WE ACHIEVE THIS?

TOP INTRODUCTION WHAT DO WE KNOW? WHAT DO WE NEED... HOW CAN WE ACHIEVE... REFERENCES

Asthma

The preceding questions will not be answered by short-term trials. Optimally, follow-up should continue into adulthood, as childhood respiratory illness affects later respiratory health in adulthood.

Relationship between markers and short- and long-term outcome. The relationship between indices of inflammation (with and without treatment), symptoms, and lung function is not known and is likely to be complex. Large long-term population studies (from infancy to adolescence), in which measurements of inflammatory markers and lung function are made serially, would define this relationship. Comparisons could be made between current symptom pattern and severity and the inflammatory marker. In addition, the ability of each type of measurement to predict future outcome could be sought. Currently available epidemiological evidence of long-term prognosis of wheezing throughout childhood is inadequate to make a risk-benefit assessment on the advisability of treatment, as there are minimal data concerning severity. Although symptoms disappear in the majority of children before adulthood, 75% of children attending hospital for asthma continue to wheeze past puberty (S. Pedersen, unpublished observation, 1999).

Effect of early treatment of evidence of inflammation on long-term outcome. A randomized controlled trial of antiinflammatory treatment in children with their first wheezy episode associated with evidence of persisting inflammation after recovery, would answer the question as to whether early treatment of inflammation alters outcome. The trial should include serial measurements of inflammatory markers, with treatment continued until no evidence of inflammation was seen for a predetermined period of time (e.g., 6 mo). Follow-up through childhood would be needed to determine the effect on long-term prognosis.

Other Conditions

A measure of airway inflammation has not been incorporated into clinical trials in conditions of airway inflammation other than asthma. Long-term trials assessing an inflammatory marker would determine if the abolition of inflammation was a useful therapeutic goal in conditions such as early cystic fibrosis or bronchiectasis. Currently, antiinflammatory therapy is almost routinely instituted in these conditions without evidence that it alters either short- or long-term prognosis.

	Footnotes

Correspondence and requests for reprints should be addressed to Nicola Wilson, M.D., Department of Paediatrics, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: n.wilson{at}rbh.nthames.nhs.uk

	References

TOP INTRODUCTION WHAT DO WE KNOW? WHAT DO WE NEED... HOW CAN WE ACHIEVE... REFERENCES

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