American Journal of Respiratory and Critical Care Medicine

Asthma

The definition of asthma has changed from that of a clinical disease (wheeze and/or cough in a setting where asthma is likely and other, rarer conditions have been excluded) (1) to a combination of clinical symptoms and pathology, usually describing airway inflammation (2). The concept of including inflammation in the definition has been questioned (3). In young children it is impractical to include inflammation as a requirement for the diagnosis.

We know that a large part of the asthma phenotype in young adults at least is related to helper T type 2 (Th2) lymphocyte- and eosinophil-mediated airway inflammation, but even in atopic adult asthma other important mechanisms may be involved (4, 5). These may include noneosinophilic inflammation (neutrophils or other cells, chemical mediators acting directly on the airway, neurogenic inflammation, plasma extravasation) and the effect of a possible reduction in baseline airway caliber, either for developmental reasons or secondary to acquired remodeling (6). In the context of other childhood wheezing illness, both bronchoscopic (7) and blind (8) lavage studies suggest that pure virus-associated wheeze is not an eosinophilic disease and is not even due to or associated with chronic airway inflammation. Other evidence suggests that the eosinophil may not always be the main cell involved in airway inflammation. The neutrophil is an important component of the late-phase response (9) and of endotoxin-induced asthma (10). Furthermore, a subgroup of patients with asthma without elevated sputum eosinophil levels and who were poorly responsive to corticosteroids has been described (11). Finally, there may be significant differences in the pathology of severe and mild to moderate asthma (12).

We also know that the treatment with inhaled or oral corticosteroids of what is presumed to be airway inflammation in children reduces blood markers of T cell activation and cytokine levels (13) and reduces sputum eosinophilia (14) and nitric oxide (NO) levels (15). This suggests that antiinflammatory treatment reduces some forms of airway inflammation. There is a poor correlation between these markers when they are used to measure the response to antiinflammatory therapy (16).

Uncontrolled trials in children (17) and controlled studies in adults (18) indicate that a delay in the initiation of inhaled corticosteroid therapy for the treatment of chronic asthma results in poorer long-term lung function. This suggests that untreated inflammation leads to secondary airway remodeling, which becomes irreversible. However, there are few data on the relationship between early inflammatory processes and structural changes in the airways of patients with asthma. We also know that corticosteroids are not disease modifying in chronic childhood asthma, at least when started at the conventional time. Even after 2 yr, the plateau for bronchial hyperreactivity is not reached and relapse occurs if treatment is stopped (19).

Cystic Fibrosis

Cystic fibrosis (CF) is characterized by chronic inflammation, which is predominantly neutrophilic in character, and chronic infection. The latter is usually attributable to Staphylococcus aureus and Haemophilus influenzae in the first instance, followed by Pseudomonas aeruginosa and sometimes Burkholderia species. Bronchoalveolar lavage (BAL) studies suggest that infection and inflammation occur early on in life in infants with CF (20, 21). There is dispute as to whether infection is a necessary prerequisite for inflammation, or whether the CF airway is intrinsically proinflammatory (22). Antiinflammatory therapy with oral corticosteroids halts the deterioration in pulmonary function in children colonized with P. aeruginosa (23); however, data on inhaled corticosteroids are conflicting (24, 25). The nonsteroidal antiinflammatory agent ibuprofen may be useful in patients with CF (26). It has been suggested that treatment with oral macrolides, which have a number of nonantimicrobial effects, including reduction of interleukin 8 (IL-8) release from bronchial epithelial cells (27), may be promising in CF (28). In the Far East, erythromycin is effective in the treatment of adults with diffuse panbronchiolitis, which is characterized by a neutrophilic BAL and chronic infection with P. aeruginosa (29). Other causes of bronchiectasis (e.g., primary ciliary dyskinesia, immunoglobulin deficiency) are also characterized by chronic airway inflammation, but have been studied in less detail. It is unclear when inflammatory damage becomes irreversible.

Chronic Lung Disease of Prematurity

Data from blind BAL studies have shown that neutrophil trafficking into the airways and release of proinflammatory cytokines occur in children born prematurely, and continue together with failure of neutrophil apoptosis in those individuals who go on to develop chronic lung disease of prematurity (CLD) (30-33). Neutrophil trafficking appears to start soon after birth, and its antecedents are probably antenatal (32). The early use of parenteral corticosteroids reduces the prevalence of CLD and the associated mortality, but adverse effects of this treatment are a problem (34). Inhaled corticosteroids may improve lung function (35), aid extubation (36), and reduce the need for parenteral corticosteroids (37), but do not prevent CLD (38, 39). Inhaled steroids are widely used in long-term oxygen-dependent babies, but there is no evidence of a clinical benefit or an effect on ongoing inflammation.

Preterm babies are exposed to numerous adverse stimuli, including the effects of prematurity itself, oxygen-enriched mixtures, positive pressure ventilation, and parenteral corticosteroids. It is not clear which of these stimuli is responsible for the initiation or potentiation of airway inflammation (or whether there is another underlying cause) and which of these histological changes are due to the direct effects of agents on the lung and which are secondary to airway inflammation. Most studies have been conducted in infants at the severe end of the spectrum (by definition, because they are postmortem) and little is known of any changes in the mildest cases. The processes of resolution of inflammation and repair of lung damage have barely been investigated.

Asthma

Basic mechanisms. Currently, there is insufficient evidence to draw any firm conclusions regarding the mechanism of airway inflammation in asthma. First, we have no idea whether the events that initiate airway inflammation are the same as those that subsequently sustain the disease. We do not know if there are critical “all or nothing” triggers, as seen, for example, in the onset of occupational asthma in response to a specific work-related allergen. The process of occupational asthma may become self-sustaining even after removal of the offending allergen (40). Second, we have insufficient evidence to determine which of the several possible mechanisms of asthmatic inflammation are relevant in ongoing pediatric asthma. Although the vast majority of children with asthma can be treated safely and effectively with low to moderate doses of inhaled corticosteroids, a few children remain symptomatic despite high-dose treatment. The asthma treatment guidelines for these children are haphazard and not evidence based (lower steps are at least not haphazard); we need a greater understanding of the underlying phenotypes in order to rationalize treatment in this difficult group. Third, are the mechanisms involved in pure virus-associated wheeze the same as those operative in virus-induced exacerbations of chronic asthma?

We also need to know whether occult infection may be a factor in asthma. An analogy is peptic ulcer disease; this was once thought to be due to hypersecretion of gastric acid but is now treated effectively with antibiotics against Helicobacter pylori.

Measuring inflammation. It might be useful to measure airway inflammation in the context of diagnosis and treatment. Nonspecific respiratory symptoms are frequently diagnosed as asthma and inhaled corticosteroids are prescribed. A diagnostic test of airway inflammation would put this on a more scientific basis.

When following up known patients with asthma we rely on surrogates such as symptoms and pulmonary function to determine the dose of antiinflammatory medication without actually measuring airway inflammation. This is rather like treating hypertension without measuring blood pressure. We need to have a portable, easy to use, rapid, desk-top “inflammometer,” and to determine whether measuring inflammation directly or indirectly enables us to treat asthma more effectively. A controlled 2-yr study of adults showed that treating the deterioration in bronchial hyperreactivity (a surrogate marker for inflammation), even though symptoms and conventional physiology were stable, resulted in fewer exacerbations and less airway remodeling (demonstrated by bronchial biopsy). This was at the cost of a greater total use of inhaled corticosteroids (41). This lends support to the view that an “inflammometer” of some sort could improve asthma management.

Importance of residual inflammation. Studies using induced sputum (42, 43) and blood (44) have shown that there is evidence of residual inflammation even after using conventional treatment to produce a satisfactory clinical response. We need to know whether this is of long-term importance to the child, and if so, whether this is true for all children with airway inflammation, or whether a residual factor is needed to convert smoldering inflammation to airway damage.

Relationship between inflammation and remodeling. It has been assumed that airway inflammation causes airway remodeling. However, in one bronchoscopic study (published as an abstract) of children with nonspecific symptoms, bronchial biopsy showed early onset of remodeling, independent of the duration of symptoms (45). This implied that the two processes (remodeling and inflammation) may proceed independently and at different rates. One could hypothesize that it might be possible to treat inflammation without removing the underlying stimulus to airway remodeling. Furthermore, we need to know whether all types of inflammation are associated with, or result in, remodeling. For example, does recurrent virus-induced neutrophil infiltration have any residual effect? If not, then investigation of those inflammatory processes that do not cause remodeling may be fruitful. Methods to monitor the remodeling process that are applicable to routine clinical care are also required.

Many of the factors necessary for normal growth are also involved in the inflammatory process and its resolution. We need to know whether efforts to control this process may unwittingly result in adverse effects on normal growth. Also, does the potential plasticity of the developing lung convey protection against early damage, or is the damage during this critical period irreversible?

Cystic Fibrosis

If we are to intervene to prevent chronic infection with any organism, but particularly with P. aeruginosa, we need to know which occurs first—inflammation or infection. Furthermore, if the airway in CF is proinflammatory, an early clinical trial of an antiinflammatory medication at first diagnosis of CF would be justified. Antiinflammatory medications are needed that are better tolerated than oral corticosteroids and more active against neutrophils.

Why is the CF airway vulnerable to specific pathogens, in particular P. aeruginosa? Hypotheses variably rely on preceding inflammation being present. One theory is that altered fluid composition on the airway surface (which varies with inflammation) may inactivate cationic peptides on the airway surface (46). Another is that the receptor for P. aeruginosa, asialo-GM1, may be upregulated (47) and its affinity increased by pseudomonal neuraminidase resulting in increased binding (48). Another view is that preceding inflammation and epithelial injury result in disruption of tight junctions, increased epithelial cell internalization of P. aeruginosa, and thus established infection (49).

Chronic Lung Disease of Prematurity

What is the time of onset of this inflammatory process within the airway, and is antenatal intervention possible? What processes result in the failure to reduce inflammatory cell trafficking within the airway? Corticosteroids do not prevent CLD, and therefore we need to discover new agents that modulate this inflammatory process.

In patients with CLD there are concerns about the effects of the disease and its treatment on lung growth. Further studies are needed in this respect.

How long does inflammation persist in CLD, and are long-term inhaled corticosteroids justified in this group?

The previous sections have highlighted a lack of knowledge in a large number of important areas. This final section touches on only a few suggested areas for further study.

1. Clinical tools are needed to measure the effect of treatment on airway inflammation, and whether this approach is worthwhile in the short and long term. Such tools should ideally be noninvasive, simple to use, not require patient cooperation, directly reflect the different types of inflammation, and give a rapid answer (like a peak flow meter). One technique that meets some of these criteria is the measurement of exhaled NO in asthma. Prospective trials should be conducted to determine whether monitoring NO facilitates more effective asthma management, both in terms of exacerbations and long-term lung function. Only a long-term study would show whether treating a well asthmatic child with a high NO level is beneficial or not. However, it is still unclear whether a single marker will ever be satisfactory (5), even in subgroups of patients with asthma.

2. New agents are required for the treatment of steroid- insensitive and noneosinophilic inflammation, as well as agents that can favorably modulate neutrophil inflammation. This is likely to be achieved with a better understanding of the basic control mechanisms in the pediatric airway. Leukotriene (LT) synthesis blockade (but not receptor antagonism) reduces neutrophil chemotaxis via its effects on LTB4. However, there are also other neutrophil chemoattractants, including interleukin 8. It is clear that steroids are not the answer to this problem; indeed, they may even reduce neutrophil apoptosis (50).

3. Our knowledge of airway remodeling in children is virtually nonexistent. We do not know which aspects of inflammation initiate remodeling, what sustains the process, or whether it is reversible with time or treatment. There is an urgent need to identify noninvasive surrogates of airway remodeling in order to perform longitudinal studies in individual children; possible techniques might include induced sputum with measurement of growth factor (e.g., transforming growth factor β); high-resolution CT scanning; or some form of breath analysis. These should be correlated with the gold standard, namely bronchial biopsy, and opportunities to carry out biopsy studies should actively be sought. This information is necessary to monitor the effects of any treatment such as inhaled steroids.

4. A top priority is to make every effort to define the inflammatory phenotypes of asthma in more detail, using the techniques described in this workshop, rather than slavishly assuming that what may be true in adults (but probably is not) is ipso facto true in children. Studies of animals, even of the young, need to be interpreted critically. Animal models are best suited to the investigation of individual pathways, a rather reductionist approach, rather than to modeling the complexities of the integrated inflammatory pathways in children. Together with this, we need to study remodeling in these different diseases.

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Correspondence and requests for reprints should be addressed to Andrew Bush, M.D., Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail:

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