The continuous laryngoscopy exercise test in severe or in difficult-to-treat asthma in adults: a systematic review

Figures & data

Figure 1. Flowchart of the search results.

Table 1. Summary of the included studies involving objectives, study design, study population and methods.

Reference number	Objectives	Study design	Study characteristics	Subjects (number, age, gender, lung function)	Controls (number, age, gender)	Methods
Heimdal 2006 (1)	To assess the diagnostic feasibility and patient acceptance of a test for exercise-induced upper airway flow limitation.	Clinical case-control study	N = 16 n (females) = 10 (63%) n (treated with medication for asthma) = 4 n (EILO) = 4 Follow-up period: cross-sectional study	n = 4 Age range 15–20 years n (females) = 4 (100%) n (treated with medication for asthma) = 4 (100%) n (EILO) = 4	n = 12 Age range 21–29 years n (females) = 6 (50%) n (treated with medication for asthma) = 0 n (EILO) = 0	CLE test to symptom-limiting exhaustion, treadmill, metabolic ergo-spirometry.
Christensen 2011 (5)	To assess the prevalence and symptoms of EILOs and their relation to airway hyperresponsiveness (AHR).	Interventional study	N = 98 n (females) = 61 (62%) n (study individuals with diagnosed asthma) = 21 (21%) n (EILO) = 42 Follow-up period: cross-sectional study	N = 98 Mean age (min-max)18.48 (14–24) years, OR (females/males) = 1.61 (95% CI 1.03–2.50), median age 19 years, n (study individuals with diagnosed asthma) = 21 (21%), n (EILO) = 42	None	Self-reported and interview-based questionnaire about EILO and exercise-induced asthma (EIA) symptoms, bronchial provocation test, maximal physical stress test on a treadmill, CLE test with video recording.
Nielsen 2013 (6)	To evaluate the prevalence of EILO in athletes with exercise-induced respiratory symptoms.	Retrospective cohort study	N = 88 n (females) = 50 (56.8%) n (study individuals with diagnosed asthma) = 38 (43%) n (EILO) = 31 Follow-up period: cross-sectional study	N = 88. The median (IQR) age 17 (9.0) years. n (females in EILO group) = 24/31 (77%), n (females in non-EILO group) = 26/57 (46%). n (subjects with diagnosed asthma in EILO group) =12/31 (39%), n (subjects with diagnosed asthma in non-EILO group) = 26/57 (46%)	None	Skin-prick tests, methacholine challenge, mannitol test, eucapnic hyperventilation test, CLE, treadmill ergo-spirometry. Diagnosis of asthma was based on the presence of symptoms and a positive bronchoprovocation test (BPT) or bronchodilator reversibility test.
Røksund 2009 (7)	To explore laryngeal response pattern to exercise by CLE test in patients with exercise-induced inspiratory stridor.	Observational study	N = 171 n (females) = 112 (65%) n (treated with medication for asthma) = 130 (76%) n (EILO) = 113 Follow-up period: cross-sectional study	n (patients) = 151, Mean (SD) age 16.3 (7.3) years, n (females) = 99 (66%), n (treated with medication for asthma) = 128/151 (85%), n (EILO) = 113	n (asymptomatic volunteers) = 20, Mean (SD) age = 22.7 (7.8) years, n (females) = 13 (65%), n (treated with medication for asthma) = 2/20 (10%), n (EILO) = 0	CLE test to symptom-limiting exhaustion on a treadmill, film recordings of the larynx and upper part of the body, breathing sounds recordings.
Tervonen 2009 (8)	To development and validate a diagnostic method for exercise-induced vocal cord dysfunction by combining continuous fiberoptic laryngoscopy with bicycle ergometry test.	Validation study	N = 45 n (females) =34 (76%) n (study individuals with diagnosed asthma) = 13 (29%) n (EILO) = 5 Follow-up period: cross-sectional study	n (patients) = 30 Median (min-max) age 27.8 (10.6–69.2) years n (females) = 24 (80%) n (subjects with diagnosed asthma) =13 (43%), n (EILO) = 5	n (controls) = 15, healthy individuals Median (min-max) age 33.4 (20.9–54.1) years n (females) = 10 (67%) n (controls with diagnosed asthma) = 0 n (EILO) = 0	CLE test in a bicycle ergometer. A questionnaire on medical history. Diagnosis of asthma was based on GINA guidelines.
Walsted 2017 (9)	To evaluate if inspiratory flow parameters could predict the presence of EILO in the patients with suspected asthma.	Interventional study	N = 37 n (females) = 20 (54%) n (study individuals with diagnosed asthma) = 23/37 (62%) n (EILO) = 8 Follow-up period: cross-sectional study	N = 37, Age range 15–45 years, Patients with asthma or with suspected asthma and exercise symptoms. Subjects with >10 pack-years were excluded. Non-EILO: n = 29, median (IQR) age 27.0 (22), female/male = 12/17 EILO: n = 8, median age (IQR) = 22.5 (12), female/male = 8/0, n (subjects with diagnosed EILO and asthma) = 5/8 (63%).	None	Methacholine or mannitol test, skin prick tests, FeNO, CLE test, treadmill ergo-spirometry. Diagnosis of asthma was based on symptoms and bronchial hyperreactivity (if FEV1 > 70% of expected) or on specialist evaluation, including bronchodilator reversibility, PEF variation, symptoms, and asthma history.

Study characteristics comprises the total number of the study population (N) (symptomatic study subjects and controls), whereas Subjects the number of symptomatic study subjects (n) and Controls number of controls (n).

Table 2. Summary of the included studies involving summary measures, main results, and bias.

Reference number	Summary measures	Results	Bias	Limitations
Heimdal 2006 (1)	Adduction of the supraglottic structures and of the vocal cords was assessed by video at rest, at moderate exercise, and at maximal effort. Respiratory noise and external pictures were taken to assess respiratory distress. Clinical symptoms and tolerability of the test were assessed by a questionnaire.	In maximal exercise, moderate supraglottic adduction in 4/4, slight glottis adduction in 2/4 cases, moderate in 1/4 and severe in 1/4 case. Slight supraglottic adduction was found in 2/12 of controls.	2/4 cases were adults. 3/4 cases had been treated with β2-agonists and 1/4 with inhaled corticosteroids. No information on asthma test results.	Limited size of the study population. Absence of severity of asthma.
Christensen 2011 (5)	FEV1, FVC, PD20. Degree of EIL and EI-VCD by visually based severity grading system (0–3) and EILOMEA method.	EILO was confirmed in 10/21 patients with asthma (47.6%). No symptoms specific for either AHR or EILO were found.	Inhalation of 1 mg terbutaline (Tubuhaler) prior to the physical stress test. Timing of the symptoms was unobserved. OR (symptomatic female/symptomatic male participating in CLE test) = 3.1.	Absence of level of laryngeal obstruction, lung function values and severity of asthma. Self-reported data of diagnosis of asthma.
Nielsen 2013 (6)	Diagnosis of EILO was based on the presence of symptoms and a Norwegian grade score ≥2 (i.e. at least moderate).	EILO was diagnosed in 35.2% of athletes. Supraglottic EILO appeared in 25% of all athletes, glottic EILO in 3.4%, and combination in 6.8%. Diagnosis of asthma was positive in 12 (38.7%) of the EILO and 26 (45.6%) of the non-EILO participants.	Day-to-day variability of EILO. Fluctuation of airway hyperresponsiveness. β2-agonist before warm-up. Subjectivity of evaluation by Norwegian standardized scoring system. No controls.	Limited size of the study population. Absence of level of laryngeal obstruction for patients with asthma. Absence of lung function values separately for study individuals with asthma and severity of asthma.
Røksund 2009 (7)	Peak VO2, FEV1 (% pred), FVC (% pred), PEF (% pred), max heart rate (% pred). Glottic and supraglottic movements were scored throughout the exercise session according to the protocol of Maat et al (13).	113/166 (68%) patients had moderate or severe laryngeal findings in CLE test. Adduction typically started within supraglottic structures. Treatment for asthma during the year preceding the CLE test was reported by 2/20 (10%) volunteers and by 128/166 (77%) patients. 82/166 (49%) patients reported no effect from asthma medication on exercise-related symptoms. 20/20 (100%) volunteers exhibited a normal laryngeal response pattern to exercise.	Treatment for asthma during the year preceding the CLE test was reported by 10% of the volunteers and by 68% of the patients. Information on whether the medication was discontinued before the examination was absent. There was no information if diagnosis of asthma was confirmed in those with treatment for asthma.	Only usage of treatment for asthma was reported instead of confirmed diagnosis of asthma. Absence of lung function values separately for study individuals with asthma and severity of asthma.
Tervonen 2009 (8)	Supraglottic and glottic laryngeal adduction was graded on a four-stage scale (described by Maat et al). Heart rate (% of maximum), changes in respiratory rate, blood pressure, FEV1, and SaO2, total duration of the test, ECG.	Nine patients showed signs of diagnostic or highly suspect exercise-induced vocal cord dysfunction; this was not observed in the controls. The test was successfully performed for 27 (90%) of the patients and all controls.	Subjectivity when visually estimating obstruction. Three patients >60 years of age were tested.	Limited size of the study population. Absence of level of laryngeal obstruction. Absence of lung function values and severity of asthma. No description of how many of the patients with asthma had EILO.
Walsted 2017 (9)	Supraglottic and glottic obstruction level, FEV1, FVC, FEV1/FVC, bronchial and extrathoracic airway hyperresponsiveness to mannitol, methacholine, and bronchodilator reversibility. Diagnosis of asthma was based on the consistent symptoms and a positive bronchoprovocation test (BPT) and in those with no BPT (i.e. if baseline FEV1 < 70%) on symptoms, bronchodilator reversibility, peak flow variation (>20%), and history of asthma. Extrathoracic airway hyperresponsiveness was defined as a decrease in FIF50 of at least 25%. The CLE video recordings were graded applying the Norwegian standardized scoring system by two specialists and diagnosis of EILO was based on grade score ≥2 (moderate) for either glottic or supraglottic obstruction.	8/37 (22%) had EILO. 18/29 were asthma positive (62%) of non-EILO participants and 5/8 (63%) of EILO participants. Based on the CLE test 8 (22% of all females) had EILO, of whom 7 (88%) had supraglottic and 1 glottic EILO. Subjects with EILO had a slightly higher FEV1/FVC ratio (0.89 vs 0.83: p = 0.01). There was no difference in age, level of physical activity, pulmonary function test values (including bronchial provocation test results) between EILO and non-EILO subjects or in diagnosed asthma (63% vs 62%). EILO subjects had a lower BMI (20.2 vs 23.6; p = 0.04), less frequent rescue medication usage (p = 0.04), and fewer symptoms and limitations on daily activities than non-EILO subjects.	78 patients were recruited but only 37 performed CLE test. Subjects were young and physically active.	Limited size of the study population. Absence of level of laryngeal obstruction. Absence of lung function values separately for study individuals with asthma and severity of asthma.

Table 3. Summary of the included studies involving lung function.

Reference number	Spirometry	Methacholine	FeNO	Mannitol	Other	Controls (all lung function data)
Heimdal 2006 (1)	FEV1 (% pred) (min-max) 111 (92–130), FVC (% pred) (min-max) 121 (90–157), peak VO2 (min-max) 42.5 (26.4–65.8) mL/(kg·min)	No data	No data	No data	No data	No data
Christensen 2011 (5)	No data	No data	No data	No data	No data	None
Nielsen 2013 (6)	FEV1 (% pred, mean (SD)): EILO group 110.0 (18.7), non-EILO group 108.0 (23.0).	No data	n (non-EILO, FeNO >50 ppb) = 2	No data	No data	None
Røksund 2009 (7)	FEV1 (% pred) (SD) = 101.9 (15.9), FVC (% pred) (SD)= 105.7% (14.8), PEF (% pred) (SD)= 96.6% (21.0), peak VO2 (SD) = 45.1 (9.4) mL/(kg·min)	No data	No data	No data	No data	FEV1(% pred) (SD) = 103.6 (12.7), FVC (% pred) (SD)= 106.6 (10.3), PEF (% pred) (SD)= 113.5 (14.7), peak VO2 (SD)= 53.0 (8.1) mL/(kg·min)
Tervonen 2009 (8)	No data	No data	No data	No data	No data	No data
Walsted 2017 (9)	Non-EILO: FEV1 (L) median (IQR) = 3.96 (1.4), FEV1 (%) (IQR) 102.08 (20), FVC (L) (IQR) median 4.53 (1.54), FVC (%) (IQR) 124.3 (26), FEV1/FVC ratio (IQR) 0.832 (0.11). EILO: FEV1 (L) median (IQR) = 3.46 (0.9), FEV1 (%) (IQR) 97.18 (30), FVC (L) (IQR) median 3.82 (1.23), FVC (%) (IQR) 109.4 (36), FEV1/FVC ratio (IQR) 0.892 (0.11)	Non-EILO: methacholine 10/29 (34%), extrathoracic airway hyperresponsiveness: methacholine 8/29 (28%), mannitol and methacholine 1 study participant. EILO: methacholine 4/7 (57%), extrathoracic airway hyperresponsiveness: methacholine 3/7 (43%), mannitol and methacholine 0 study participants.	FeNO >25 ppb, positive/tested Non-EILO: 12/28 (43%) EILO: 2/8 (25%)	Non-EILO: mannitol positive/tested 11/27 (41%), extrathoracic airway hyperresponsiveness: mannitol 9/24 (38%), mannitol and methacholine 1 study participant. EILO: mannitol 4/8 (50%), extrathoracic airway hyperresponsiveness: mannitol 4/8 (50%), mannitol and methacholine 0 study participants.	Non-EILO: bronchodilator reversibility 1/29 (3%), asthma 18/29 (62%). EILO: bronchodilator reversibility 1/8 (13%), asthma 5/8 (63%).	None

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