Exercise-Induced Bronchoconstriction, Urticaria, And Anaphylaxis

Exercise-Induced Bronchoconstriction

• Definitions: Exercise-induced bronchoconstriction (EIB) is defined as a transient narrowing of airways in response to exercise and can be classified as with asthma (EIBa) or without asthma (EIBwa). EIB can present with classic asthma symptoms or with more subtle fatigue or effects on performance. EIB was previously defined as exercise-induced bronchospasm, as opposed to bronchoconstriction, and exercise-induced asthma (EIA) described symptoms brought on by exercise in those with underlying asthma. The expert consensus is that EIB is now defined as noted earlier, with the two subtypes EIBa and EIBwa. Objective evidence of bronchial hyperresponsiveness in response to exercise should be included alongside symptoms when diagnosing EIB. In those without a confirmed diagnosis of asthma, measured decrease in forced expiratory volume in 1 second (FEV ₁ ) of 10% or more in response to a bronchoprovocation challenge can be used to diagnose EIB.

• Epidemiology: Approximately 5%–20% of the total population experiences EIB, but it is more common in athletes, particularly elite athletes. Forty-one percent of people with a history of allergic rhinitis experience EIB. Forty to ninety percent of asthmatics have exercise-related symptoms. EIB occurs equally between both genders and can develop at any age. The prevalence of EIB is highest among high-ventilation sports, particularly in cold-weather sports and swimming.

• Risk factors: A history of asthma is the biggest risk factor for EIBa. Other EIB risk factors include allergic rhinitis, a family history of atopy, cold-weather sports, and sports that require a sustained high ventilation rate (e.g., Nordic skiing, soccer, and distance running). Swimming has a particularly high risk because of the high ventilation rate and exposure to chlorine by-products.

• Mechanism: Current understanding of the pathophysiology of EIB is that dry air leads to osmotic changes at the airway surface. This hyperosmolar environment causes mast cell degranulation and the release of mediators that cause bronchoconstriction and airway inflammation. The release of neuropeptides from sensory nerves may also play a role.

• Triggers:

  • Oral breathing

  • Dry, cold air

  • Environmental pollutants and allergens

  • Intense exercise

  • Chemicals such as chlorine in pools, pesticides, and fertilizers

• Clinical signs and symptoms: Symptoms usually develop within 15 minutes after 5–8 minutes of intense exercise and resolve within 30–90 minutes. There can be a late-phase response that occurs 4–8 hours after exercise. Symptoms can be brought on with all strenuous activity or only in certain environments like extreme cold. Those with EIBa may experience symptoms that extend into nighttime or early morning and symptoms brought on by other triggers outside of exercise such as upper respiratory infections (URIs) and seasonal environmental allergens

  • Wheezing

  • Shortness of breath

  • Coughing

  • Chest tightness

  • Chest pain (usually reported in children)

  • Increased mucus production

  • Poor athletic performance

  • Fatigue

• Physical examination: May include the following on examination:

  • Lungs: wheezing (particularly expiratory phase with wheezing at rest consistent with asthma); rales or rhonchi

  • Skin: signs of atopic disease such as eczema

  • Nose: enlarged and boggy turbinates

  • Throat: cobblestoning and enlarged tonsils

  • Sinus: tenderness on pressure

• Testing: EIB should be diagnosed based on both signs and symptoms in addition to objective testing, but not one without the other. EIBa can be identified by spirometry with standard asthma testing protocols. Initial testing for EIB should be spirometry with assessment of bronchodilator response. In well-conditioned athletes, spirometry alone may appear normal, so checking response to a short-acting beta-agonist is a critical part of the test. Reversibility is defined as an increase in FEV ₁ of more than 200 mL and ≥12% from baseline. This cutoff may not be appropriate to use in younger children. If spirometry is not diagnostic, then bronchoprovocation testing should be done ( Table 37.1 ). This can be done using direct (methacholine or histamine challenge) or indirect challenges, including exercise challenge tests (ECTs), eucapnic voluntary hyperpnea (EVH) challenge, hypertonic saline challenge, inhaled adenosine monophosphate (AMP) challenge, and inhaled mannitol powder challenge. EVH is considered the gold-standard test for EIB and is advised by the International Olympic Committee (IOC) but is not widely available. Exercise challenge testing is another option but carries low sensitivity and can be unreliable. In children and adolescents, particularly in those without signs of asthma or response to EIB treatment, one should consider cardiopulmonary exercise testing to look for other causes of their symptoms.

  Table 37.1

  Wada-Approved Bronchial Provocation Tests for Diagnosing EIB

  Bronchial Provocation Test	Decrease in FEV 1 for Positive Test Result
  Eucapnic Voluntary Hyperpnea	>10%
  Methacholine Aerosol Challenge	>20%
  Mannitol Inhalation (not available in the United States)	>15%
  Hypertonic Saline Aerosol Challenge	>15%
  Exercise Challenge (field or laboratory)	>10% at any two consecutive time points
  Histamine Challenge	>20% during graded test of 2 minutes

  EIB, Exercise-induced bronchospasm; FEV ₁ , forced expiratory volume in 1 second; WADA, World Anti-Doping Agency.

• Types of testing:

  • Exercise challenge test: Testing should be ideally performed for 8 minutes, allowing the athlete to reach 85% of peak heart rate by 2 minutes and maintaining the same for another 6 minutes. Spirometry is done at baseline and specific time intervals after exercise. Sport-specific field testing may be needed, particularly in winter sports, especially if laboratory-based testing is not diagnostic and/or environmental factors need to be reproduced.

    • Free running/skiing

      • Advantages—Cost-effective, requires minimal cardiovascular (CV) monitoring

      • Disadvantages—Depending on the season, difficult to control environmental factors such as temperature and humidity and may not trigger EIB in all patients

    • Treadmill/cycle ergometer

      • Advantages—CV and pulmonary monitoring can be performed during the workout. Workload can be standardized.

      • Disadvantages—Expensive equipment needed; may not represent environment in which symptoms occur.

    • Bronchial provocation testing

      • The patient inhales a substance designed to induce bronchoconstriction. Examples include EVH challenge, hypertonic saline challenge, inhaled AMP challenge, and inhaled mannitol powder challenge. It may be used as a primary diagnostic test or when exercise challenge is equivocal. EVH testing is performed by having the athlete ventilate 22–30 times per minute for 6 minutes using dry air containing 5% carbon dioxide.

    • Other testing:

      • Skin testing: can be helpful if clinically indicated, as there is a strong correlation between allergies and EIB/EIA

      • Chest radiograph or computed tomography (CT) chest: may show signs of underlying lung disease

      • Echocardiogram/other cardiac testing: if a CV abnormality is a possible cause of the symptoms

• Medications and testing: When performing tests, certain medications (e.g., inhalers, leukotriene receptor antagonists) must be avoided or stopped at least 8–24 hours before testing so as to not confound the testing and produce false-negative results.

• Differential diagnosis:

  • Exercise-induced laryngeal dysfunction (EILD):

    • EILD, also called exercise-induced laryngeal obstruction (EILO), was previously known as paradoxical vocal cord motion disorder (PVCM) or vocal cord dysfunction (VCD) and describes the transient glottic closure associated with physical activity ( Fig. 37.1 ).

      

    • EILD symptoms typically occur at maximal effort and resolve quickly with cessation of exercise. Subjects usually have inspiratory wheezing and/or stridor as opposed to EIB and asthma, which primarily produce expiratory wheezing. The stridor in EILO occurs because of paradoxical closure of the vocal cords. Patients complain of difficulty “getting air in” and difficulty in breathing. EILO is frequently misdiagnosed as asthma and warrants special consideration in the diagnosis of EIB. It can also exist alongside EIB. Symptoms of EILO usually do not respond to inhaled beta-agonists.

    • The diagnosis of EILO is often made based on clinical presentation with description or video of symptoms. A flow-volume loop obtained while the patient is symptomatic can show flattening of the inspiratory loop. Continuous laryngoscopy during exercise, which allows visualization of vocal cord adduction on inspiration, is considered the gold standard of diagnostic testing for EILO. Treatment is reassurance, education, avoidance of triggers, and speech therapy for breathing techniques.

  • Gastroesophageal reflux disease (GERD):

    • May present with atypical symptoms such as chronic cough and wheezing

    • Consider in athletes who have symptoms of GERD or worsening symptoms of EIB associated with regurgitation, large meals, or alcohol

  • Swimming-induced pulmonary edema (SIPE):

    • SIPE presents with shortness of breath and cough during or immediately after swimming with associated evidence of pulmonary edema.

    • Spirometry reveals an acute restrictive pattern, with changes lasting up to 1 week.

  • Other:

    • General deconditioning

    • Other obstructive or restrictive pulmonary disorders

    • Cardiovascular conditions

    • Exercise-induced anaphylaxis

    • Pulmonary embolism

• Prevention and treatment:

  • Nonpharmacologic treatment and prevention

    • Conditioning may help reduce symptoms and severity of EIB.

    • Short burst of vigorous exercise (e.g., 30-second bouts) may be used to treat EIB and induce short-term refractoriness, which is attributed to endogenous release of prostaglandins and depletion of constrictive mediators.

    • Warming up before activity induces bronchodilation and refractoriness to EIB.

    • Cooling down after strenuous exercise decreases EIB symptoms after exercise.

    • Avoid hyperventilation.

    • Cold weather may exacerbate EIB; hence, dressing appropriately may help. In addition, in cold weather, a buff or breath warming device may help retain warmer and more humid air, thereby reducing EIB symptoms.

    • Avoid exercising in areas that have high pollen counts or heavy pollution, as air quality inversely correlates with exercise-induced respiratory symptoms.

    • Avoid vigorous activity when the patient has a cold or when allergies are not well controlled.

    • Use nasal breathing (as opposed to mouth breathing) to help warm the air when exercising.

    • Dietary modifications, including low salt, and supplementing with omega-3 fatty acid intake and vitamin C, are thought to reduce symptom severity.

    • Caffeine has bronchodilatory properties and modulates respiratory dynamics by decreasing physiologic dead space and increasing tidal volume.

    • Breathing control training, such as yogic breathing, may also be considered.

  • Pharmacologic

    • Inhaled beta-adrenergic agonists: Prevention and treatment can be achieved by using a short-acting beta ₂ -agonist (e.g., albuterol) inspired approximately 15–30 minutes before exercise; this can often prevent or reduce the symptoms of EIB. The typical dose of these medications is 90 to 180 mcg inhaled. Administration should ideally be performed using a spacer with the inhaler to maximize the concentration of the medicine; only albuterol in an aerosolized form has been shown to be effective in EIB and asthma ( Fig. 37.2 ). Chronic administration of beta-agonists may lead to tolerance, decreased medication efficacy, or decreased broncho-protection during exercise.

      

    • Leukotriene antagonists (e.g., montelukast): Can be added as an adjunct to beta-agonists or occasionally as monotherapy. Recommended dosing is 1 to 2 hours before activity; less risk of developing tolerance compared with beta-agonists.

    • Inhaled corticosteroids: Not effective in EIBwa, but the mainstay of treatment of persistent asthma; all athletes who have persistent asthma and have symptoms with exercise should be on an inhaled steroid. The measured benefit of inhaled corticosteroids may not occur until weeks after initiation of therapy. Inhaled corticosteroids with a long-acting beta-agonist (e.g., formoterol or salmeterol) may benefit athletes participating in long-term activity, such as distance runners or multiple workouts per day. Long-acting beta-agonists are not recommended as monotherapy for EIB because of risks of severe exacerbation and sudden cardiac death and have the potential for creating tolerance to beta-agonists. However, they can be found in conjunction with inhaled steroids as so-called combination therapy, and this can be of use in certain athletes.

    • Antihistamines/intranasal steroids: Both will help athletes who have underlying allergic rhinitis. Treating allergic rhinitis symptoms is a critical part of the EIB treatment plan. Athletes who follow World Anti-Doping Agency (WADA) guidelines should avoid antihistamines combined with the banned decongestant, pseudoephedrine.

    • Other medications: Cromolyn, a mast cell–stabilizing agent, can be used as an adjunctive treatment for asthma. Muscarinic antagonists, both short-acting and long-acting, cause bronchial smooth muscle relaxation and can be effective for EIB. These agents are often used with beta-agonists for asthma control independent of exercise.

    • See Table 37.2 for a list of governing bodies and their rules for pharmacologic treatment of asthma.

      Table 37.2

      Governing Bodies for Pharmacologic Treatment of Asthma

      Governing Body	Policy on EIB	Medications
      NCAA	Need documentation of diagnosis, medical history, and dosage information	Beta 2 -agonists are prohibited, unless inhaled and with a valid prescription
      World Anti-Doping Agency	It is recommended that all athletes who may be prescribed asthma medications seek a clear diagnosis from a respiratory specialist and undergo the appropriate tests to optimize management and to exclude other possible diagnoses. This is mandatory if a TUE is being sought to prescribe a systemic glucocorticoid in competition or a prohibited inhaled beta 2 -agonist in and out of competition.	All selective and nonselective beta 2 -agonists are prohibited, except inhaled salbutamol, formoterol, or salmeterol at allowable concentrations.

      EIB, Exercise-induced bronchoconstriction; NCAA, National Collegiate Athletic Association; TUE, therapeutic use exemption.