The KAAACI Standardization Committee Report on the procedure and application of the bronchial provocation tests

Kyung-Hwan Lim; Min-Hye Kim; Min-Suk Yang; Woo-Jung Song; Jae-Woo Jung; Jeongmin Lee; Dong In Suh; Yoo Seob Shin; Jae-Woo Kwon; Sae-Hoon Kim; Sang-Heon Kim; Byung-Jae Lee; Sang-Heon Cho

doi:10.4168/aard.2018.6.1.14

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Lim, Kim, Yang, Song, Jung, Lee, Suh, Shin, Kwon, Kim, Kim, Lee, Cho, and the Korean Academy of Asthma, Allergy and Clinical Immunology Standardization Committee: The KAAACI Standardization Committee Report on the procedure and application of the bronchial provocation tests

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Allergy Asthma Respir Dis 2018;6(1):14-25.

Published online: 5 January 2018

DOI: https://doi.org/10.4168/aard.2018.6.1.14

The KAAACI Standardization Committee Report on the procedure and application of the bronchial provocation tests

Kyung-Hwan Lim¹, Min-Hye Kim², Min-Suk Yang³, Woo-Jung Song⁴, Jae-Woo Jung⁵, Jeongmin Lee⁶, Dong In Suh⁷, Yoo Seob Shin⁸, Jae-Woo Kwon⁹, Sae-Hoon Kim¹⁰, Sang-Heon Kim¹¹, Byung-Jae Lee¹², Sang-Heon Cho⁴; the Korean Academy of Asthma, Allergy and Clinical Immunology Standardization Committee

¹Department of Internal Medicine, Armed Forces Capital Hospital, Seongnam, Korea

²Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea

³Department of Internal Medicine, Seoul Metropolitan Government - Seoul National University Boramae Medical Center, Seoul, Korea

⁴Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

⁵Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea

⁶Department of Pediatrics, Yonsei University Wonju College of Medicine, Wonju, Korea

⁷Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea

⁸Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea

⁹Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea

¹⁰Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

¹¹Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea

¹²Division of Allergy, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence to: Sae-Hoon Kim https://orcid.org/0000-0002-2572-5302 Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea Tel: +82-31-787-7046, Fax: +82-31-787-4052, E-mail: shkrins@gmail.com

• This research was supported by a fund (A092076) by Research of Korea Centers for Disease Control and Prevention.

Received 1 September 201715 September 2017 Accepted 19 September 2017

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Bronchial provocation tests are of value in the evaluation of airway hyperresponsiveness. Nonspecific bronchial challenge (methacholine, mannitol, exercise, etc.) is used when the symptoms, physical examination, and measurements of pulmonary function are unremarkable in the diagnosis of asthma, when a patient is suspected of having occupational asthma or exercise-induced broncho-constriction (EIB), and when a screening test for asthma or EIB is required for some occupational groups in whom bronchospasm would pose an unacceptable hazard. Methacholine inhalation challenge is most widely used pharmacologic challenge and highly sensitive. For appropriate interpretation of the results of methacholine provocation, it is important to perform the test with the standardized protocol and to recognize that inhalation methods significantly influence the sensitivity of the procedure. Indirect challenges (e.g., mannitol and exercise) correlate with airway inflammation and are more specific but less sensitive for asthma. Indirect provocation tests are used to confirm asthma, to differentiate asthma from other airway diseases, and to evaluate EIB.

Keywords: Bronchial provocation tests, Methacholine, Mannitol, Exercise test

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Table 1.

Characteristics of direct and indirect bronchial challenge tests

Measure	Direct challenge	Indirect challenge
Mechanism	Direct effect on airway receptors	Intermediate pathways by mediator release
Examples	Histamine, methacholine	Exercise, mannitol, hypertonic saline, EVH, AMP
Factors of influence
ASM function	++++	++
Airway caliber	+++	Minimal
Airway inflammation	++	++++
Dosing
Dose required	Low	High
Dose limited	No	Yes
Sensitivity	High	Low
Specificity	Low to fair (pretest probability)	High
Diagnostic value	Rule out asthma	Confirm asthma
	Help diagnose asthma, especially if symptoms mimicked	Evaluate for EIB

EVH, eucapnic voluntary hyperpnea; AMP, adenosine monophosphate; ASM, airway smooth muscle; EIB, exercise-induced bronchoconstriction.

Table 2.

Contraindications for methacholine provocation testing

Absolute contraindications
Severe airflow limitation (FEV₁ < 50% predicted or <1.0 L)
Heart attack or stroke in last 3 months
Uncontrolled hypertension
Known aortic aneurysm
Relative contraindications
Moderate airflow limitation (FEV1 < 60% predicted or <1.5 L)
Inability to perform acceptable-quality spirometry
Pregnancy or nursing mothers
Nursing mothers
Current use of cholinesterase inhibitor medication (for myasthenia gravis)

FEV₁, forced expiratory volume in 1 second.

Table 3.

Medications that may decrease bronchial responsiveness and withholding time

Factor	Example	Minimum time interval from last dose to study
Medications
Short-acting inhaled bronchodilators	Salbutamol (albuterol), terbutaline	8 hr
Medium-acting bronchodilators	Ipratropium	24 hr
Long-acting inhaled bronchodilators	Salmeterol, formoterol	48 hr
	Tiotropium	1 wk
Oral bronchodilators	Liquid theophylline	12 hr
	Intermediate-acting theophyllines	24 hr
	Long-acting theophyllines	48 hr
Leukotriene modifiers	Montelukast, pranlukast, zarfirlukast	24 hr
Antihistamines	Hydroxyzine, cetirizine	3 day
Foods	Coffee, tea, cola drinks, chocolate	Day of study

Table 4.

Medications that may inhibit response to mann and withholding time itol provocation test

Medications	Time to withhold
Inhaled mast cell stabilizers	6–8 hr
Short-acting beta 2 agonists	8 hr
Inhaled corticosteroids	12 hr
Ipratropium bromide	12 hr
Inhaled corticosteroids plus long acting beta 2 agonists	24 hr
Long-acting beta 2 agonists	24 hr
Theophylline	24 hr
Tiotropium bromide	72 hr
Antihistamines	72 hr
Leukotriene receptor antagonists	4 days

Table 5.

Interpretation of mannitol provocation test

	Patients with clinical diagnosis of asthma
	Positive for mannitol provocation		Negative for mannitol provocation
	Not using ICS	Using ICS	Not using ICS	Using ICS
Interpretation	Patient with active airway inflammation	Patient has active airway inflammation despite current ICS therapy	Airway inflammation not detected	Patient's asthma is controlled on current ICS therapy
Response or planned action	Consider using ICS	Consider increasing ICS dose, ascertain adherence to therapy	Consider alternative diagnosis	Consider maintaining or reducing dose of ICS
	Patients with suspected asthma
	Positive for mannitol provocation		Negative for mannitol provocation
Interpretation	Asthma likely		Asthma cannot be ruled out
Response or planned action	Consider using ICS		Further diagnostic work-up (e.g. peak flow monitoring)
			If symptoms are uncharacteristic, consider alternative diagnosis

ICS, inhaled corticosteroid.

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