Importance of the bronchodilator response to the diagnosis and treatment of childhood asthma

Asthma is one of the most common chronic respiratory diseases. Despite its great frequency, diagnosis and classification of asthma severity is extremely difficult. Routine measurement of lung function, and in particular the demonstration of reversibility of functional disorders, in addition to evaluation of clinical symptoms and physical examination, increase diagnostic accuracy, improve control, helps taking the right therapeutic decisions and identifying the risk of progressive loss of lung function. FEV1 is a standard indicator for measuring the function of airways in lung diseases but its role in monitoring the childhood asthma is uncertain. The evaluation of bronchodilator response (change in FEV1 after administration of p2-agonist) provides valuable information on airway lability which is traditionally used for the detection of asthma. Bronchodilator response which reflects the biomarkers of eosinophilic inflammation is a good predictor of response to ICS, and may reflect long­term prognosis and the airway remodeling, which gives a new application of pulmonary function testing in the difficult process of diagnosis and treatment of asthma in children.

Asthma is a chronic inflammatory disease of the airways involving many cells and cellular el­ements. Chronic inflammation is associated with airway hyper-responsiveness, leading to recur­rent episodes of wheezing, breathlessness, chest tightening and coughing, particularly at night and early morning. These episodes are usually as­sociated with widespread, but variable, obstruc­tion of the airways, reversible either spontane­ously or after treatment (6).

A diagnosis of asthma is usually based on the presence of characteristic symptoms. Variations in the interpretation of individual complaints of the patient can significantly affect both diagnosis and therapeutic approach. Measurement of lung function and in particular the demonstration of reversibility of functional disorders, significantly increases diagnostic accuracy, which is why cur­rent guidelines recommend routine use of spi­rometry in order to provide more objective crite­ria for diagnosis (6).

Pulmonary function testing allows assessment of the severity of airflow constriction, its revers­ibility and variability and confirmation of asthma diagnosis. Two methods are widely adopted in patients over 5 years:

• Spirometry – measurement of forced expira­tory volume in 1 sec. (FEV1) and forced vital ca­pacity (FVC);
• PEF – Measurement (PEF – peak expiratory flow) (6).

Children often have normal lung function, but can develop severe airway obstruction during acute asthma attack. This lability in lung function may reflect the underlying airway hyperreactiv­ity. In childhood there is good evidence that the baseline FEV1 % predicted is often within normal limits (12) and 80% of asthma attacks occur in children with normal FEV1 (3). Limitation of the use of FEV 1 alone in childhood asthma is demon­strated of Bacharier et al. (1) by the lack of associa­tion between the severity of symptoms, intensity of medication and the value of FEV1 % predicted. Therefore, clinical diagnosis, based on a single measured value for the pre-bronchodilator FEV1 may result in an underestimation of the diagno­sis, severity and the choice of control therapy (12).

Bronchial lability in turn could be a useful in­dicator in the diagnosis of childhood asthma. Demonstration of bronchial hyper-reactivity in the context of clinical symptoms provides further details on the mosaic of asthma diagnosis. This concept is not new. The so-called bronchial lability index was first described in 1966 from Jones in children with asthma. He defines this indicator as the total difference in FEV1 between its highest achieved value, after administration of short-acting p2-agonist and the lowest reached, after provocation with physical exercise (7). In this study, Jones found that children with the greatest bronchial lability have more frequent and more severe exacerbations, nocturnal symptoms and limitation of physical activity in a study cohort compared to children with the same baseline spi­rometry, but without increased instability.

Bronchial responsiveness to bronchodilator medications is a complex physiological response involving the airway epithelium, nerves, media­tors and bronchial smooth muscles. Bronchodila­tor response (BDR) is characterized by an increase in forced expiratory flows (including peak expira­tory flow) and volumes, and reduced airway resis­tance.

Despite the long history of BDR as diagnostic test, there are still no generally accepted rules for its conduct. According to the latest document ATS/ERS (American Thoracic Society/European re­spiratory society) TASK FORCE for the standartiza- tion of lung function tests, there is no consensus about the drug, dose and route of administration (9).

If using metered dose inhaler (MDI) it is neces­sary to meet the following requirements in order to minimize the differences between functional laboratories:

• Recommended use of a short-acting P2- agonist, such as salbutamol;
• Use four separate doses of 100 pg, adminis­tered by metered dose inhaler with a valve-hold­ing chamber (spacer);
• Repeat the test after 15 minutes.

If bronchodilator test is conducted to deter­mine the therapeutic effect of a specific drug then this drug is administered, and dosed in the same way as used in clinical practice. The time be­tween application of the drug and re-spirometry is determined by the beginning of its effect.

There is no clear consensus about what consti­tutes the reversibility in subjects with bronchial obstruction. There are three most common ways of expressing bronchodilator response:

1. as a percentage of baseline FEV 1;
2. as a percentage of the estimated value;
3. as absolute change (ml).

It has been found that change in FEV1 and/or FVC as a percentage of the estimated value has advantages over the use of percentage of base­line. When used as a criterion percent of baseline rate, most authors recommend 12-15% increase in FEV1 and/or FVC to define a significant re­sponse. Increase up to 8% (or 150 ml) is taken as a result of natural variability of the measurement. When the change is above this value, the next step is determining the threshold for clinically significant positive BDR.

Table 1. Corresponding to the BDT – standardization of methods (9).

In assessing the BDR, contemporary authors recommended the change from baseline in FEV 1 and/or FVC should be reported as a percentage and absolute terms. Unlike the output in a single study >12% and 200 ml is considered “significant” bronchodilatation. If changes in FEV 1 were not significant, reduction in lung hyperinflation may be an indicator of significant response. Failure to respond to bronchodilator testing does not pre­clude a clinical response to bronchodilator ther­apy (9).

For the past decade several teams have been working on the establishment of bronchial labil­ity by measuring the response to inhaled bron- chodilators help in the diagnosis of asthma in childhood. Galant et al. found that bronchial la­bility as measured by the response to inhaled bronchodilator may be useful in the diagnosis of childhood asthma (4). The authors demonstrate that the use of a threshold for a positive bron­chodilator response (BDR) albuterol (180pg after inhalation with MDI or nebulizers with 2.5mg) can differentiate children with asthma from those with normal history. They show that BDR distin­guishes asthmatics from non-asthmatics bet­ter than baseline FEV1 independently and most strongly by a combination of high and low FEV1 BDR. These data confirm the results of an earlier study by Dundas et al. (2), who found that 9% threshold for BDO after administration of 400 pg salbutamol/albuterol, combines the best sensitiv­ity and specificity in distinguishing “wheezing” from “non-wheezing” among a group of students in London. As noted by the study’s authors before setting the 9% threshold for BDO as a diagnostic test for asthma in children, prospective study is needed on this indicator in non-selected cohorts, because diagnostic value can vary depending on the frequency of “wheezing” in this population.

The idea of using more than the traditional threshold for BDO in childhood is further devel­oped by Galant et al., who aim to determine the relationship between poor asthma control and three different thresholds for BDR (>8%, >10% >12%) in children with normal baseline spiro­metry. Poor control is determined by the clinical index: nocturnal symptoms, need for p2-agonist, absence from school, limiting physical activ­ity. Factors that determine risk are exacerbations within the previous year (>2 days), visiting emer­gency units and hospitalizations (>1) and system­ic administration of ICS.

They found that the threshold >10% and >12% is characterized by poor control of asthma and atopy in the group of children without controlling treatment. Threshold >10% gives similar results with the classical >12% and increased identifica­tion of children with potential risk and the need for controlling treatment. Threshold >8% is also an indicator of poor control and inflammation of the airways. The authors concluded that >10% threshold is a compromise on the relationship be­tween asthma control and identification of chil­dren with potentially high risk, but only as non­controlling treatment in the last 6-8 weeks (4).

Tantisira et al. (14) studied the importance of bronchodilator and bronchoconstrictor response (BDR and BCR) as independent indicators of future lung function. According to their results broncho- constrictor response (BCR – PC20 to methacho- line) is an independent indicator of the natural course of untreated asthma and subsequent levels of lung function, regardless of treatment. BDR is an independent indicator of future lung function and a good basic indicator of therapeu­tic response and success of treatment with ICS. They reported that children with the highest BDR who are receiving inhaled corticosteroids (ICF) have the highest pre-bronchodilator FEV1 % pre­dicted after 4 year follow up. Their results show a relationship twice as strong in the group treated with ICS than that with placebo.

In another large cohort of children with mild to moderate asthma, Sharma et al. (11) showed that children with BDR stay above 12% for 4 months or 4 years of follow, have a poor prognosis with more frequent hospitalizations, more frequent use of oral CS, nocturnal symptoms, school ab­sences and lower pre-bronchodilator FEV1 at the end of the fourth year. Elevated levels of IgE, no treatment with ICS, data for airways reactivity and the baseline FEV1 % predicted the existence of a consistent BDR. Relationships established by them are valid for the 12% threshold and BDR over 10%.

Puckett et al. (10) examined the value of BDR as a predictor of increased inflammation in the large airways in mild asthma. According to them BDR reflecting bronchial lability may be consid­ered a marker of airway inflammation, remodel­ing and response to treatment with ICS in mild asthma. They demonstrate a positive relationship between BDR and eNO-signals of the proximal airways, and negative with those of the distal airways (alveolar NO concentration). Weak asso­ciation with BDR inflammation in the alveoli and distal airways is explained by scanty smooth mus­culature in the terminal bronchioles. Also estab­lished that children with BDR threshold >12% and >10% have the same clinical course in follow-up, those with BDR >12% had significant increases in FE NO which is associated with poor long-term control and increased morbidity. BDO threshold >8% is a simple method for predicting inflamma­tion of the large airways, and hence the potential response to the ICS. Szefler et al. (13) prove that patients who respond best to inhaled corticoste­roids are those with the most pronounced bronchodilator response, regardless of baseline FEV1.

The study PRICE (The Predicting Response to Inhaled Corticosteroid Efficacy trial) found that ICS are anti-inflammatory medication for persis­tent asthma with variable response – at 25-35% there is no such account or a slight improvement. Patients were divided into two groups according to the value of BDR – Responders >5% and Non­responders <5%. According to the results ob­tained lack of response to an ICS (BDR <5%), even in the short track (6 weeks), means that these pa­tients do not need ICS due to lack of therapeutic effect (8).

In conclusion, BDR is a dynamic indicator of the lability of the airways, which is traditionally used for the detection of asthma. It reflects the biomarkers of eosinophilic inflammation (eNO, bronchial and sputum eosinophills, bronchial hy­per-reactivity and atopy) is a good predictor of re­sponse to ISF, long-term prognosis and may affect remodeling of the airways. After further studies in the future study of BDR can give a new applica­tion of pulmonary function tests in the difficult process of diagnosis and treatment of asthma in children.