AMP-BPT and His-BPT for Assessment of Asthma (AMPHis)

Is Adenosine Monophosphate Superior to Histamine for Bronchial Provocation Test in Evaluation of Asthma?

Adenosine monophosphate (AMP) may reflect airway inflammation and hyperresponsiveness, but relationship between AMP and histamine (His, a conventional stimulus) bronchial provocation test (BPT) in asthma is not fully elucidated. The investigators aimed to compare both BPTs and determine their usefulness in reflecting changes of asthmatic symptoms. BPTs were performed in cross-over fashion, at 2-4day intervals. Cumulative doses eliciting 20% FEV1fall (PD20FEV1), diagnostic performance and adverse events were compared. Patients with PD20FEV1 lower than geometric mean were defined as responders, otherwise poor responders. Patients with uncontrolled and partly controlled asthma, who maintained their original inhaled corticosteroids therapy, underwent reassessment of airway responsiveness and asthmatic symptoms 3 and 6 months after.

Airway hyperresponsiveness, the pivotal feature of asthma, can be assessed by bronchial provocation tests (BPTs), which may elicit bronchoconstriction via inhalation of stimuli. Histamine has been a direct stimulus for inducing bronchoconstriction via vasodilation, eosinophil chemotaxis and tissue edema. Clinically, histamine BPT (His-BPT) has gained extensive application for decades owing to the assay sensitivity and feasibility, but could not ideally predict anti-inflammatory treatment outcomes in practice. Additionally, mild adverse events (flushing and hoarseness) and insufficient capacity of identifying exercise-induced asthma have hampered further clinical applications. Adenosine monophosphate (AMP) is an inflammatory mediator that serves as an indirect bronchial stimulus for detecting airway hyperresponsiveness in asthma. Compared with histamine, AMP may be pathophysiologically more relevant to airway inflammation and hyperresponsiveness and has been linked to presence and magnitude of atopy. However, differences of response to AMP-BPT and His-BPT in different asthma control levels and their associations with asthmatic symptom scores have not been fully elucidated. We hypothesized that asthmatic patients, regardless of control levels, responded differentially to AMP-BPT and His-BPT, and that greater reduction in airway responsiveness to AMP (esp. responders of AMP-BPT) was associated with significant symptom alleviation. Henceforth, we sought to: 1) compare diagnostic performance and safety of AMP-BPT and His-BPT in different asthma control levels; 2) determine the association between airway responsiveness and asthmatic symptom scores. Currently, His-BPT is recommended by the Chinese guideline and shares considerable similarity with methacholine (another conventional stimulus) BPT, we therefore did not perform the latter in this study.

Methods of AMP-BPT, by applying dosimeters, resembled that reported previously [see references 21-25]. Briefly, dilutions were delivered via nebulizers (output: 160 μl/min) using automated APS pro system (JAEGER, Hochburg, Germany). Inhalation challenge with normal saline served as control step. Challenge steps were proceeded if FEV1 fall <15% and restored to <10% within 1 minute. Subsequent inhalation challenges were performed at 1-minute intervals, and ceased when FEV1 fell by ≥20%. Salbutamol was administered via spacer (Volumatic, Allen & Hanbury's, UK). Spirometry was reexamined at minutes 3, 5, 10 and thereafter, to ensure safety, before discharge.

Methods of His-BPT, by applying dosimeters, resembled that reported previously [see references 21-25]. Briefly, dilutions were delivered via nebulizers (output: 160 μl/min) using automated APS pro system (JAEGER, Hochburg, Germany). Inhalation challenge with normal saline served as control step. Challenge steps were proceeded if FEV1 fall <15% and restored to <10% within 1 minute. Subsequent inhalation challenges were performed at 1-minute intervals, and ceased when FEV1 fell by ≥20%. Salbutamol was administered via spacer (Volumatic, Allen & Hanbury's, UK). Spirometry was reexamined at minutes 3, 5, 10 and thereafter, to ensure safety, before discharge.

Patients with uncontrolled and partly controlled asthma, following accomplishment of study 1, were invited to participate in observational study (study 2), which sought to determine usefulness of both BPTs in reflecting improvement of asthmatic symptoms following 3 and 6 months of moderate-dose ICSs treatment (400~800μg budesonide or equivalent). Patient continued to administer their original ICS during follow-up. During two follow-up visits (3 months apart), AMP-BPT, His-BPT and Hogg's symptom scores were reassessed.

Asthma symptom score recorded within 1 week, with the highest possible score of 42 for the whole week

Maximal decrease in FVC following bronchial provocation, expressed as percentage as compared with baseline levels

Maximal decrease in FEV1 following bronchial provocation, expressed as percentage as compared with baseline levels

Maximal decrease in MMEF following bronchial provocation, expressed as percentage as compared with baseline levels

Maximal decrease in PEF following bronchial provocation, expressed as percentage as compared with baseline levels

Diagnostic performance of AMP-BPT and His-BPT (area under the receiver operation characteristic curve, sensitivity, specificity, Youden index)

Inclusion Criteria: aged 18~65 years; nil respiratory infection within 3 weeks; normal chest radiography; baseline FEV1>60% predicted; withdrawn from, if any, oral leukotriene modifiers, corticosteroid or anti-histamine for 5 days, oral xanthenes or long-acting bronchodilators for 2 days, inhaled corticosteroids (ICSs) for 24 hours, and salbutamol for 6 hours Exclusion Criteria: FEV1 fall ≥20% following saline inhalation; other chronic lower respiratory diseases (i.e. COPD); severe systemic diseases (i.e. uncontrolled hypertension, malignancy); limited understanding. For healthy subjects, they had to be aged 18~65 years and had nil respiratory infection within 3 weeks, systemic diseases and had normal lung function.

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