Severe Persistent Asthma

Aka: Severe Persistent Asthma, Severe Asthma, Difficult to Treat Asthma, Difficult-To-Treat Asthma

1. See Also
   1. Asthma
   2. Asthma Evaluation
   3. Asthma Differential Diagnosis
   4. Asthma Education
   5. Asthma Management
   6. Mild Intermittent Asthma
   7. Mild Persistent Asthma
   8. Moderate Persistent Asthma
   9. Asthma Exacerbation
2. Definitions
   1. Uncontrolled Asthma
      1. Frequent use and early refills of rescue Inhaler
      2. Rescue Inhaler use more than twice weekly
      3. Awakening with nighttime symptoms more than twice monthly (over age 5)
      4. Within last 12 months, two or more courses of oral Corticosteroids, or Asthma hospital admission
   2. Difficult-To-Treat Asthma
      1. Uncontrolled Asthma despite high-dose Inhaled Corticosteroid with second controller or
      2. Uncontrolled Asthma despite oral Corticosteroids
   3. Severe Asthma
      1. Subset of Difficult-To-Treat Asthma
      2. Uncontrolled Asthma despite medication and lifestyle compliance or unable to taper maximal medical therapy
3. Criteria: Severe Asthma
   1. Continuous symptoms throughout the day, interfering with sleep and activity
   2. Frequent exacerbations (several times daily)
      1. Daily symptoms throughout the day
      2. Nightly symptoms
         1. For age <5 years, night awakenings more than once per week
      3. Beta Agonist use several times daily
      4. Oral Corticosteroids required 2 or more times per year
   3. Pulmonary Function Tests
      1. FEV1 or PEF <60% of predicted
      2. PEF variability > 30%
      3. FEV1 to FVC Ratio decreased >5% (<75% for age 5-19, <70% for age 20-39, <65% for age 40-59, then <60%)
4. Management: General
   1. See Asthma Stepped Care
   2. Evaluate for Non-compliance with medical therapy or lifestyle changes
      1. See Asthma Education
      2. Evaluate Inhaler technique
         1. See Asthma Inhaler Education
      3. Review Asthma Action Plan at every visit
      4. Consider Environmental Allergen exposures
      5. Tobacco Cessation and eliminate Secondhand Smoke exposure
      6. Consider Allergic Occupational Asthma
      7. Confirm filling of prescriptions and use as directed
         1. Ask about barriers to use (e.g. excessive cost)
      8. Consider medication adverse effects (e.g. NSAIDs, Aspirin, Beta Blockers)
      9. Consider comorbid conditions (e.g. Congestive Heart Failure, Coronary Artery Disease)
   3. Rule out Other Causes
      1. See Asthma Differential Diagnosis (e.g. Cystic Fibrosis)
      2. Repeat Spirometry or full Pulmonary Function Tests
      3. Consider high resolution CT Chest (e.g. chronic Pulmonary Embolism, Interstitial Lung Disease)
      4. Consider bronchoscopy
   4. Long-term daily control medication
      1. Inhaled Corticosteroid (High dose) and
      2. Long acting beta agonist Bronchodilator (LABA) and
         1. Formoterol when used as maintenance LABA, may be used as rescue Inhaler as well (2020 Asthma guidelines)
            1. See Single Maintenance and Reliever Therapy (SMART Asthma Management Protocol)
      3. Leukotriene Receptor Antagonist (Montelukast)
         1. Montelukast is associated with increased risk of Major Depression and Suicide
            1. https://www.fda.gov/news-events/press-announcements/fda-requires-stronger-warning-about-risk-neuropsychiatric-events-associated-asthma-and-allergy
      4. Consider Zileuton (Zyflo)
      5. Consider Systemic Corticosteroids (2 mg/kg/day to 60 mg/day)
   5. Other measures
      1. Short term rescue with beta agonist
      2. See Asthma Biologic agents below
      3. See Breathing Exercises in Asthma
      4. Bronchial Thermoplasty
         1. Bronchoscopy delivered radiofrequency ablation to airway Smooth Muscle
         2. Decreases bronchoconstriction and airway hyperplasia
         3. Improves Asthma quality of life, but worsens Asthma in first 6 weeks after treatment
         4. Torrego (2014) Cochrane Database Syst Rev (3): CD009910 +PMID:24585221 [PubMed]
         5. Thomson (2019) J Asthma Allergy 12:375-87 +PMID:31819539 [PubMed]
5. Management: Asthma Biologic Agents
   1. See Asthma Monoclonal Antibody
   2. Indicated in refractory, Type 2 Asthma (Allergic Asthma, represents 50% of Asthma)
   3. Indications: One of the following present
      1. Blood Eosinophils >150/uL
      2. Sputum Eosinophils >2%
      3. Ferrous Nitrous Oxide >20 parts per billion
      4. Maintenance oral Corticosteroids required
   4. Preparations: Anti-IgE
      1. Omalizumab (Xolair)
         1. May be used in age 6 years old and older
         2. Indicated in severe refractory (Step 5-6) Asthma with IgE levels >75
         3. Subcutaneous Injection every 2-4 weeks
   5. Preparations: Anti-IL5 (Interleukin 5)
      1. Mepolizumab (Nucala)
         1. May be used in age 12 years old and older
         2. Administered SQ every 4 weeks
      2. Benralizumab (Fesenra)
         1. May be used in age 12 years old and older
         2. Administered SQ every 4 weeks for 3 doses, then every 8 weeks
      3. Reslizumab (Cinqair)
         1. May be used in age 18 years old and older
         2. Administered IV every 4 weeks
   6. Preparations: Interleukin-4 Alpha Receptor Antagonist
      1. May be used in age >= 6 years old
      2. Dupilumab (Dupixent)
         1. Adult Dose: 600 mg SQ once, then 300 mg SQ every 2 weeks
   7. Monitoring
      1. Re-evaluate every 3-6 months
      2. Taper off oral Corticosteroids and other add-on management
6. Management: Exacerbations
   1. See Asthma Exacerbation
   2. See Asthma Exacerbation Home Management
   3. See Emergency Management of Asthma Exacerbation
   4. See Asthma Inpatient Management
   5. See Status Asthmaticus
   6. See Asthma Exacerbation Severity Evaluation
   7. See Asthma-Related Death Risk Factors
7. Prevention
   1. Asthma Education
   2. Influenza Vaccine
   3. Weight loss in Obesity
   4. Exercise
8. References
   1. Park (2017) Asthma Updates, Mayo Clinical Reviews, Rochester, MN
   2. (1997) Management of Asthma, NIH 97-4053
   3. (1995) Global Strategy for Asthma, NIH 95-3659
   4. Kalister (2001) West J Med 174:415-20 [PubMed]
   5. Kemp (2001) Am Fam Physician 63(7):1341-54 [PubMed]
   6. Narasimhan (2021) Am Fam Physician 103(5): 286-90 [PubMed]
   7. Pollart (2009) Am Fam Physician 79(9):761-7 [PubMed]