Patient case: 58-year-old male with gastrointestinal stromal tumor; genetic feature: KIT (exon 9 502_503 duplication)

Clinical trial: Bronchodilator Response in 4-12 Years Chinese Controller Naive Asthmatic Children

Summary: Objectives:
  Our goal is trying to identify an ideal BDR cutoff point for Chinese controller-naïve asthmatic children. In order to achieve this, several steps need to taken.
  1. To observe BDR distribution curve for Chinese non-asthmatic children from 4-12 years
  2. To observe BDR distribution curve for Chinese controller-naïve asthmatic children from 4-12 years
  3. To compare BDR values between non-asthmatic group and controller-naïve asthmatic group, and analyze appropriate cut-off point value
  Hypothesis:
  1. Publications and our clinical experience indicate BDR value is affected by ethnicity, and children are less responded to bronchodilator compared with adult patients. From this aspect, data from Chinese children may be different from data included in the guidelines which mostly determined by studies in adults
  2. Reversible bronchospasm is a characteristic in asthma patients. Between asthmatics and non-asthmatics, different response to BDR test would be observed, and there would be a cutoff point with good sensitivity and specificity to differentiate asthmatics from non-asthmatics
  Background and rationale:
  According to the guideline of global initiative for asthma, global strategy for asthma management and prevention (GINA) and guideline of United States National Asthma Education and Prevention Program (NAEPP) guidelines spirometry, including baseline forced expiratory volume in 1 second (FEV1) and the bronchodilator response (BDR) to short acting beta agonists (SABA), should be used in children as objective measures to establish the diagnosis and severity of bronchial asthma. Spirometry is necessary because not every child came to the clinic with typical symptoms and the objective measurement can improve diagnosis confidence. Baseline FEV1, the so called "gold standard" for evaluating airway obstruction in adults, is usually in the normal range (greater than 80% predicted) in children, regardless of asthma severity. This substantially limits its value for diagnosis and assessment of response to treatment. Because of this, several other objective measures have been suggested for diagnosis and treatment in children, including the response to a bronchodilator, which reflects not only airway reversibility, but also a marker of airway inflammation.
  The current definition for a positive BDR is >12% reversibility and >200 ml increase from initial FEV1 after short acting beta-agonist (SABA) has been used. However, recent reports and our clinical observation revealed that, in a significant part of Chinese asthmatic children, their BDR value cannot achieve 12% in the evaluation.
  It has been suggested that the cutoff point of 12% is too conservative for pediatric patients. In the study carried out by Galant et al among 51 non-asthmatic children and 346 controller naïve asthmatic children between 4-17 years, the BDR value could achieve 12% in only 30.6% asthmatic children, across all severity. Meanwhile, when observing BDR value in the above study, results were 2.2% (95% CI, 0.2-4.3) in the non-asthmatic group compared with 8.6% (95% CI, 7.5-9.8) in the asthmatic group. The range seen was 7.6% (95% CI, 5.8-9.5) for mild asthma to 10.1% (95% CI, 7.6-12.6) in the severe persistent group. Also, in a study among 142 children between 5-10 years in UK, 9% increase in FEV1 after bronchodilator use was suggested as the cutoff point with good sensitivity and specificity. Moreover, in a study carried out among 3052 children in rural area between 8-15 years in Anhui Province in China, results showed BDR was 3 +/- 5% in non-asthmatic children, and 7 +/- 9% in asthmatic children.
  Difference between the proposed study to be carried out in our hospital and the one in Anhui Province is that subjects in this proposed study are from 4-12 years old, which is the largest patient segment in our clinic including preschool and school students. And most importantly, the main purpose of study in Anhui is to observe the BDR range of the non-asthmatic children and asthmatic children, while in our study, besides this objective,our will tentatively calculate a BDR cutoff point by using receiver operating characteristic (ROC curve). And the cutoff point can be used as a reference indicator in asthma diagnosis and long-term management.
  The current BDR cutoff point of 12% that is not ideal for children can also be reflected in the clinical management. It has been shown that a persistent BDR value, even less than 12%, in asthmatic children suggests poor clinical outcome. In a 4 years study among 1041 asthmatic children in America carried out by Sharma et al, it showed that compared with individuals who had a BDR of 12% and 200ml, individuals who had a BDR of 10% had similar poor clinical outcomes (e.g. more hospital visits, more prednisone bursts, increased nocturnal awakenings, and missing more days of school). Same results were also obtained in Galant et al study among 679 asthmatic children among 5-18 years.

Detailed description: This is a prospective observational non-interventional clinical study.
  1. Patient population:
  Three hundred non-asthmatic and 300 asthmatic children will be recruited.
  1. Non-asthmatic group: healthy children from 4-12 years will be recruited from the Capital Institute of Pediatrics nearby schools
  Inclusion criteria:
  1. Willingly attend this investigation
  2. Chest physical tests are normal
  Exclusion criteria:
  1. The child had been hospitalized for any severe respiratory condition
  2. A physician had ever stated that the child had asthma, reactive airway diseases, or the child had taken antiasthma medications for symptoms
  3. The child was diagnosed with congenital heart disease requiring surgery or medications for management
  4. There are positive responses concerning other serious chest problems, chest surgery, chronic productive cough, recurrent intractable wheezing, and shortness of breath
  5. The children can not finish the test that met American Thoracic Society criteria for preschool children in a maximum of 6 attempts and are unable to successfully complete post-bronchodilator (BD) spirometry
  2. Asthmatic group: 4-12 years old asthmatic children will be recruited from the asthma clinic of the Capital Institute of Pediatrics
  Inclusion criteria:
  1. Diagnose asthma by specialist of asthma (based on symptoms): criteria for the diagnosis of asthma made by the asthma specialist included a history of recurrent coughing, wheezing, or shortness of breath at rest or with exercise, symptomatic improvement after bronchodilator use, and exclusion of other diagnoses
  2. Asymptomatic or mild symptomatic with no physical signs of wheeze at the time of testing
  3. Not receiving controller medication 6 weeks prior to the initial evaluation
  4. Willing to attend this investigation
  Exclusion criteria:
  1) Using short β2 agonists within 6 hours 2) Using long acting β2 agonists within 24 hours 3) Can not finish the test that met American Thoracic Society criteria for preschool children in a maximum of 6 attempts and are unable to successfully complete post-bronchodilator spirometry.
  2. Preparation before tests
  1) Sign the consent form. 2) Fill the asthma severity form according to NEAPP guideline (asthmatic group).
  3) Chest physical test, record on the form of test. 4) Standing height and weight will be measured. 5) Calculation of age: The date of test subtracts the date of birth.
  3. Pulmonary function tests
  Standardized pulmonary function tests will be conducted.
  Contents of tests:
  Pre and post flow volume: forced volume vital capacity (FVC), FEV0.5, FEV1, FEV1/FVC ratio, PEF, forced expiratory flow 25 (FEF25), FEF50, FEF75, FEF25-75, forced expiratory time (FET), back-extrapolated volume (VBE), VBE/FVC.
  The BDR is based on pulmonary function measurements before and after administration of 2.5 mg albuterol by nebulizer. BDR is calculated as [(postbronchodilator FEV1- baseline FEV1)/baseline FEV1] x 100%.
  Study Procedures:
  1. Spirometry preparation The spirometry was purchased from VIASYS Healthcare, Hochberg Germany (MasterScope).
  1. Check: Before switch on, check the conjunction between flow sensor and the hand knob, ensure that the black compact is tightness.
  2. Calibration: Before calibration, the room temperature, pressure, humidity should be tested and recorded and all of the parameter should be reconciled to BTPS condition.
  Using 2 liters scalar to calibrate flow. Every day do the even flow calibration. Every week do the flow linear calibration, include high, media and low flow these three different flow calibration. The variety should be less than 3%.
  The record of calibration should be printed, and the technician should be signed on it and save it.
  2. Test method The training process is the same as Eigen H. et al (ref 8). The entire instruction and testing session for each child is strictly limited to 15 min, during which time children are instructed in the techniques of spirometry and performed at least three forced vital capacity maneuvers. A highly experienced children's pulmonary function technologist does the instruction for each child. At the time of testing, each child is given an explanation of the testing procedure individually and then tested using coaching techniques used in our pulmonary function laboratory in evaluating younger children.
  3. Criteria for accepting Data (ATS/ERS 2005) The principles of spirometry quality control in preschool children are the same as for adults.
  1. It is necessary to visually inspect the flow-volume and volume-time traces, and exclude maneuvers that are visibly inadequate. Maneuvers should be excluded if the flow-volume curve does not demonstrate a rapid rise to peak flow, or a smooth descending limb, with no evidence of cough or glottis closure.
  2. The start of test should be quantified by calculating the VBE. Some investigators reported that more than 80% of the studied preschool population achieved a VBE of less than or equal to 80 ml or less than 12.5% of the FVC. Alternative criteria are presented, but these should be viewed as a guide to assist visual inspection, rather than as exclusion criteria.
  3. The end of test should be quantified by reporting the point of cessation of flow. It is known that many preschool children cannot sustain forced expiration for 1 second, let alone the 6 seconds previously stipulated for adults (ref 9) , and the forced expired time should be reported but should not be used to exclude maneuvers. This pattern should not be misinterpreted as early termination (ref 10).

Eligibility: -Non-asthmatic group: healthy children from 4-12 years will be recruited from the Capital Institute of Pediatrics nearby schools
  Inclusion criteria:
  1. Willingly attend this investigation
  2. Chest physical tests are normal
  Exclusion criteria:
  1. The child had been hospitalized for any severe respiratory condition
  2. A physician had ever stated that the child had asthma, reactive airway diseases, or the child had taken antiasthma medications for symptoms
  3. The child was diagnosed with congenital heart disease requiring surgery or medications for management
  4. There are positive responses concerning other serious chest problems, chest surgery, chronic productive cough, recurrent intractable wheezing, and shortness of breath
  5. The children can not finish the test that met American Thoracic Society criteria for preschool children in a maximum of 6 attempts and are unable to successfully complete post-bronchodilator (BD) spirometry
  -  Asthmatic group: 4-12 years old asthmatic children will be recruited from the asthma clinic of the Capital Institute of Pediatrics
  Inclusion criteria:
  1. Diagnose asthma by specialist of asthma (based on symptoms): criteria for the diagnosis of asthma made by the asthma specialist included a history of recurrent coughing, wheezing, or shortness of breath at rest or with exercise, symptomatic improvement after bronchodilator use, and exclusion of other diagnoses
  2. Asymptomatic or mild symptomatic with no physical signs of wheeze at the time of testing
  3. Not receiving controller medication 6 weeks prior to the initial evaluation
  4. Willing to attend this investigation
  Exclusion criteria:
  1. Using short β2 agonists within 6 hours
  2. Using long acting β2 agonists within 24 hours
  3. Can not finish the test that met American Thoracic Society criteria for preschool children in a maximum of 6 attempts and are unable to successfully complete post-bronchodilator spirometry.

Relevance to patient case: not relevant