I have patient who has had multiple episodes of severe difficulty breathing within 3-5 minutes of beginning to run. I believe these episodes may be due to exercise-induced angioedema of her airway, but of course there are other possibilities including VCD, EIB, hysteria, and deconditioning. I would like to determine if she currently has bronchial hyper-reactivity, but I am afraid to do this with an exercise challenge.

My questions are: for the patient described below, is it reasonable to do methacholine inhalation testing? Would it be safer or less safe to do eucapnic voluntary hyperventilation testing? Which test would be more pertinent? Is there any experience in doing these tests on patients with exercise induced anaphylaxis, or does this spectrum contraindicate such testing?

Her clinical picture follows:
The patient is a 19 year old female. Every time she runs she develops a feeling of swelling in her throat, specifically in the back of her tongue. If she stops running it gradually subsides. Her worst episode was 6 years ago when her coach told her to run thru it. She became so breathless she became dizzy and leaned against a tree where she actually blacked-out. She was out for at least a minute, when some other runners came to her aid. She did not collapse to the ground, but did experience urinary incontinence while out. There was no post-ictal state and has been no recurrence involving CNS, so no EEG was ever done. Her cardiac status including EKG was subsequently normal. Although baseline spirometry was normal she was suspected to have EIA and given albuterol for prn use. She never found any relief from it, and eventually abandoned her sport. Spirometry is still normal, but lately she is somewhat short of breath with mild activity. She is not and has never been clinically sensitive to any food. She typically ran in the morning before breakfast, so food associated exercise-induced anaphylaxis is not particularly suspected, but food specific IgE levels are being checked.


Thank you for your inquiry.

First of all, in direct answer to your questions, yes, it is certainly reasonable to do an inhaled challenge test for exercise-induced asthma. There is no contraindication to the performance of this type of test in your patient. However, I would suggest that you do a mannitol challenge. As you can see from the abstracts copied below, both methacholine and mannitol are useful in this situation, but the mannitol challenge is far easier to do and much quicker. Also, as opposed to methacholine, which is a direct challenge via an effect on smooth muscle, mannitol mimics exercise more accurately since mast cell degranulation occurs in both. We utilize this test in-office in preference to methacholine challenge testing. Our patients prefer it as do our nurses. I would also prefer it over eucapnic hyper-ventilation.

Secondly, I think there are other diagnoses you should consider as demonstrated in the abstracts copied below. I don't think that exercise angioedema or anaphylaxis is likely in this patient, and in our experience, one of the most likely diagnoses is supraglottic airway collapse or laryngochalasia. Unfortunately, to make a diagnosis of this condition requires someone skilled in performing fiberoptic laryngoscopy pre- and post-exercise. The Journal of Allergy and Clinical Immunology has four excellent articles dealing with this condition. I have copied the references for you below. There is a video available demonstrating the use of this technique.

In summary, it is doubtful that your patient has angioedema due to exercise (or exercise anaphylaxis), and I think you are correct that it does not sound like she has exercise-induced asthma. In our experience, upper airway collapse or tracheal lesions (eg tracheal stenosis) are the most common entities to consider, and the references that we gave you are illustrative of these conditions, and demonstrate the use of endoscopy during exercise to establish the diagnosis.

Finally, there is no contraindication to doing a chemical asthma challenge, and the preferred test in my opinion is a mannitol challenge.

Thank you again for your inquiry and we hope this response is helpful to you.

Ann Allergy Asthma Immunol. 2000 Nov;85(5):387-91.
Exercise-induced laryngochalasia: an imitator of exercise-induced bronchospasm.
Björnsdóttir US, Gudmundsson K, Hjartarson H, Bröndbo K, Magnússon B, Juliusson S.

Rev Mal Respir. 2002 Oct;19(5 Pt 1):641-3.
[Exercise-induced laryngomalacia].
[Article in French]
Chemery L, Le Clech G, Delaval P, Carré F, Gogibu J, Dassonville J.
Author information
Service des Explorations Fonctionnelles, Hôpital Pontchaillou, CHRU de Rennes, Rennes, France.
Exercise-induced laryngomalacia is a rare differential diagnosis of exercise-induced asthma. We report the case of a previously fit 14-year-old female patient who presented with dyspnoea on intense exertion and whose condition had not improved with treatment prescribed for a misdiagnosed exercise-induced asthma. A diagnosis of exercise-induced laryngomalacia was eventually made when a variable extra-thoracic airway obstruction on the flow-volume loops was obtained after an incremental exercise test. Flexible fiberoptic rhinolaryngoscopy confirmed this abnormality and demonstrated an anterior prolapse of the arytenoid region, partially obstructing the airway. The patient therefore underwent laser aryepiglottoplasty which produced a satisfactory anatomical outcome in the larynx but which only resulted in a partial functional improvement. Laryngomalacia is rare and its pathophysiology is not well understood. However, it should be considered in patients presenting with exertional dyspnoea, particularly if there is inspiratory embarrassment, who fail to improve with beta-2-adrenergic agonists. The diagnosis can be made from the flow-volume loop and direct laryngoscopy, before and after exercise.

J Voice. 2012 Nov;26(6):779-84. doi: 10.1016/j.jvoice.2012.01.004. Epub 2012 Jun 19.
Diagnosing aerodynamic supraglottic collapse with rest and exercise flexible laryngoscopy.
Dion GR, Eller RL, Thomas RF.
Author information
Department of Otolaryngology, Head & Neck Surgery, Brooke Army Medical Center, San Antonio, Texas, USA.
Objective: Laryngomalacia is best known as a self-resolving infantile disorder characterized by inspiratory stridor with occlusion of the larynx by collapse of arytenoid tissues due to Bernoulli forces. Adult laryngomalacia has been sporadically described in the literature. We identified a series of patients with aerodynamic supraglottic collapse mimicking laryngomalacia in our Otolaryngology clinic.
Study Design: Case series.
Methods/Patients: A series of five patients from our Otolaryngology clinic with aerodynamic supraglottic collapse presented with complaints ranging from noisy breathing to dyspnea with exertion. Diagnosis was made using rest and exercise flexible laryngoscopy.
Results: Symptoms resolved in all patients who underwent traditional or modified supraglottoplasty.
Conclusions: These patients, all with abnormal corniculate/cuneiform motion occluding the airway during forceful inspiration, reinforce the diagnostic role of rest and exercise flexible laryngoscopy in patients with dyspnea and stridor. These results may suggest that aerodynamic supraglottic collapse is an underdiagnosed clinical entity.

Respir Res. 2009 Jan 23;10:4. doi: 10.1186/1465-9921-10-4.
Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma.
Anderson SD, Charlton B, Weiler JM, Nichols S, Spector SL, Pearlman DS; A305 Study Group.
Collaborators (24)
Boushey H, Casale T, Ford L, Greos L, Halverson P, Hampel F, Korenblat P, Irani AM, Matz J, Nayak A, Ostrum N, Pearlman D, Pedinoff A, Prenner B, Qaqundah P, Quesada J, Ratner P, Rundell K, Shapiro G, Sorkness C, Spector S, Tan R, Weinstein S, Ziering R.
Author information
Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia.
Background: Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma.
Methods: 509 people (6-50 yr) were enrolled, 78% were atopic, median FEV1 92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a > or = 10% fall in FEV1 on at least one of two tests, to methacholine a PC20 < or = 16 mg/ml and to mannitol a 15% fall in FEV1 at < or = 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results.
Results: Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV1 in subjects positive to exercise was 19%, (SD 9.2), mannitol PD15 158 (CI:129,193) mg, and methacholine PC20 2.1(CI:1.7, 2.6) mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive.
Conclusion: In this group with normal FEV1, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations.

Four references:
1. Tilles SA, and Inglis AF. Masqueraders of exercise-induced vocal cord dysfunction. Journal of Allergy and Clinical Immunology Vol. 124, Issue 2, Pages 377-378.e. August 2009.

2. Bjornsdottir US. Exercise-induced laryngeal prolapse in elite athletes - "curable asthma." Journal of Allergy and Clinical Immunology Vol. 113, Issue 2, Supplement, Page S271; February 2004.

3. Lim K and Li JT. Exertional dyspnea and inspiratory stridor of 2 years duration: A tale of 2 wheezes. Journal of Allergy and Clinical Immunology Vol. 113, Issue 2, Supplement, Page e10; November 2011.

4. Davis RS, Brugman SM, and Larsen GL. Use of videography in the diagnosis of exercise-induced vocal cord dysfunction: A case report with video clips. Journal of Allergy and Clinical Immunology Vol. 119, Issue 6, Pages 1329-1331; June 2007.

Phil Lieberman, M.D.

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