Asthma

Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Diagnosis is confirmed with a pulmonary function test showing a reversible obstructive pattern. Treatment, based on symptom severity, includes bronchodilators and inhaled corticosteroids for control of inflammation. Biologic agents targeting inflammatory mediators have been developed for severe persistent asthma.

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Definition and Epidemiology

Definition

Asthma is a chronic inflammatory disorder of the airways:

  • Involving many cells and cellular elements (mast cells, eosinophils, neutrophils, T lymphocytes, macrophages, and epithelial cells) 
  • Characterized by recurrent episodes of coughing, wheezing, breathlessness, and chest tightness 
  • Associated with episodic airflow obstruction, which is often reversible (spontaneously or with treatment)

Epidemiology

  • Affects approximately 8% of the population in the United States
  • Most common chronic disease of childhood with peak presentation at 3 years of age
  • Male-to-female ratio is 2:1 in childhood but this reverses in late adulthood.
  • Some cases of childhood asthma resolve in adolescence, but in those with severe asthma, the condition returns by adulthood.

Etiology

Predisposing factors for asthma

  • Host risk factors:
    • Genetics
      • Studies of families show heritability of asthma.
      • Multiple genes and environmental influence complicate genetic studies.
    • Atopy
      • Genetic predisposition to produce immunoglobulin E (IgE) antibodies on allergen exposure
      • Strong risk factor for asthma
    • Perinatal factors (increased asthma risk)
      • Prematurity at birth
      • Neonatal or early abnormality of lung function
    • Sex
      • Asthma is more common in boys before puberty. 
      • 1:1 ratio in adulthood, with women affected more by age 40
      • Unclear if sex hormones are linked to development of asthma
    • Obesity: ↑ risk of asthma 
  • Maternal factors
    • Decreased risk of asthma:
      • Increasing maternal age at delivery (> 30 years)
      • Breastfeeding: ↓ wheezing in the first 2 years of life
    • Increased risk of asthma:
      • Maternal diet: low in vitamin D and omega-3 polyunsaturated fatty acid
      • Poorly controlled maternal asthma
      • Prenatal exposure to maternal smoking
  • Environmental factors
    • Respiratory infections early in life: 
      • 40% have asthma/wheezing later in life.
      • Commonly from respiratory syncytial virus, human rhinovirus
    • Pollution: living close to a major road and ↑ nitrogen dioxide → ↑ asthma 
    • Smoking (including secondhand smoke)
    • Occupational exposure (fires, pesticides, industrial agents) 
    • Allergens (fungi, dust mite, cockroach allergen)
    • Early exposure to pet allergens: 
      • Varied results
      • Protects by decreasing sensitization to pet allergens
      • In some, asthma develops, possibly influenced by other exposures (tobacco, pollution).

Asthma triggers

In established asthma, different triggers may exacerbate the symptoms. These include the following:

  • Environmental and drug-induced:
    • Allergens
    • Cold air
    • Paints and fumes
    • Irritant gasses
    • Air pollution
    • Drugs (beta blockers and aspirin)
  • Endocrine:
    • Premenstrual hormones
    • Thyrotoxicosis
    • Hypothyroidism
  • Behavioral and psychological:
    • Exercise
    • Hyperventilation
    • Stress
  • Other triggers:
    • Upper respiratory tract infections
    • Gastroesophageal reflux

Pathophysiology

Predominant inflammatory response

  • Initial exposure to antigen:
    • Prompts naive T-cell differentiation to T helper (Th) 2 cells
    • Followed by production of IgE antibodies, which bind to mast cells and basophils (ready to respond on antigen rechallenge)
  • Early phase: inhaled antigen (presented by dendritic cells): IgE-bound mast cells and basophils degranulate (early-phase reaction) → release of mediators (prostaglandin D₂, histamine, leukotrienes) → airway smooth muscle contraction → airway tightening
  • Late phase: recruitment of inflammatory cells: Th2 cells → production of mediators and cytokines
    • IL-5: ↑ differentiation of eosinophils (which migrate to the lungs) 
    • IL-3, IL-4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) prolong eosinophil survival.
    • IL-4 also helps with T-cell differentiation and IgE production.
    • IL-13 increases mucus glands, airway fibrosis, and remodeling.
    • Eosinophils (the most prominent cells) increase the release of inflammatory mediators.
  • Effects:
    • Cellular response → airway inflammation
    • Airway smooth muscle contraction and edema, with mucus plug formation → airway obstruction
    • Increased histamine, airway smooth muscle mass, sensitivity of neural pathways with exaggerated airway constriction → airway hyperresponsiveness
    • Structural changes (smooth muscle hyperplasia and hypertrophy, increased extracellular matrix) affect reversibility of obstruction → airway remodeling

Other mechanism

  • Non-eosinophilic 
  • Does not involve Th2 cells
  • Environmental factors (pollution, smoking, infections, allergens) → involve Th1 and Th17 cell responses → neutrophilic inflammation and airway hyperresponsiveness
  • Neutrophilic inflammation: 
    • High sputum neutrophil counts
    • Associated with severe asthma exacerbations
    • Often difficult to treat and less responsive to corticosteroids

Heterogeneity of asthma

  • Asthma types based on triggers and etiology:
    • Allergic (atopic) or extrinsic asthma
      • Typically prevalent in childhood
      • Triggered by environmental allergens
    • Non-allergic or intrinsic asthma
      • Onset in adulthood
      • Various triggers: infection, exercise, aspirin 
  • Asthma is now believed to have more phenotypes, with a classification based on underlying pathophysiologic mechanism:
    • Th2–mediated (T2 high) inflammation: associated with eosinophilia and steroid responsiveness
    • Non-Th2 (non-T2): no eosinophilia, with sputum neutrophils (or normal eosinophils and neutrophils) and non-response to steroids
  • Implication: Treatment options are available and under development based on pathophysiology.

Clinical Presentation

Symptoms

  • Recurrent wheezing
  • Dyspnea: chest tightness/heavy weight on the chest
  • Cough: 
    • Can be dry or productive of sputum
    • Worse at night and in the early morning hours
  • Episodic, can resolve spontaneously or with treatment
  • Symptoms occur with characteristic triggers (i.e., allergens, cold air).

Signs

  • Asymptomatic when under control
  • When symptomatic:
    • Tachypnea, tachycardia
    • Expiratory ± inspiratory wheezing and rhonchi
    • Prolonged expiratory phase of respiration

Classification of asthma based on severity

ComponentClassification
IntermittentPersistent: mildPersistent: moderatePersistent: severe
Symptoms≤ 2 days/week> 2 but < 7 days/weekDailyThroughout the day
Short-acting bronchodilator use≤ 2 days/week> 2 days/weekDailySeveral times/day
Nighttime awakenings≤ 2/month3–4/month≥ 1/weekNightly
Activity limitationNoneMinorSomeExtreme
Lung functionFEV1 > 80%FEV1 > 80%FEV1 60%–80%FEV1 < 60%
FEV1: forced expiratory volume in 1 second

Diagnosis

Clinical findings

  • Recurrent episodes of airflow obstruction or airway hyperresponsiveness are present.
  • Airflow obstruction is at least partially reversible. 
  • Alternative diagnoses are excluded.

Pulmonary function tests

  • Spirometry:
    • Maximal inhalation followed by rapid forceful exhalation (at least 6 seconds)
    • Measures: 
      • FEV1 (forced expiratory volume in 1 second)
      • FVC (forced vital capacity or the maximal volume exhaled with maximally forced effort)
    • ↓ FEV1 and FEV1/FVC ratio < 0.70 (suggests airway obstruction)
  • Bronchodilator response:
    • Nebulized or 2–4 puffs of bronchodilator (e.g., albuterol) given, then spirometry rechecked after 15 minutes
    • Increase in FEV1 by > 12% or 200 mL (bronchodilator responsiveness)
  • Peak expiratory flow (PEF):
    • Maximal inhalation, then fast forceful exhalation (< 2 seconds) into peak flowmeter
    • A single peak flow is obtained during symptoms.
    • Results compared with average normal values (based on height and age)
    • Post-bronchodilator administration, improvement of > 20% suggests airway obstruction (favors diagnosis of asthma)
    • Used more for monitoring than for diagnosis
  • Bronchoprovocation testing:
    • A stimulus (methacholine, exercise, histamine, inhaled mannitol) is tried, to trigger bronchoconstriction.
    • ≥ 20% reduction in FEV1 with challenge/testing (airway hyperresponsiveness)
  • Impulse oscillometry (IOS):
    • For children < 5 years old or those who cannot perform spirometry
    • Passive measurement of lung mechanics
    • Requires minimal patient cooperation, but not available to many clinicians

Exhaled nitric oxide

  • Nitric oxide measured in patient’s exhaled breath
  • Basis of test: eosinophilic airway inflammation upregulates nitric oxide synthase → ↑ amount of fraction of exhaled nitric oxide (FENO)
  • FENO > 50 parts per billion: 
    • Indicates eosinophilic airway inflammation 
    • Improves with inhaled corticosteroid (ICS)
  • Limitations:
    • Asthma is not always due to eosinophilic airway inflammation.
    • Lower FENO: cannot exclude use of ICS (as it provides benefit even for mild asthma)
    • Affected by smoking, atopy, age, and sex

Chest X-ray

  • Excludes other diagnosis (pneumothorax or pneumonia in exacerbations)
  • Normal in mild asthma
  • May show hyperinflation in severe asthma (flattened diaphragm, wide intercostal spaces)
  • Indicated for atypical presentation of asthma (fever, crackles, hypoxemia)

Additional tests

  • No blood test can confirm diagnosis of asthma.
  • Complete blood count: may show eosinophilia (which suggests atopic asthma)
  • IgE level: 
    • Moderate-to-severe asthma
    • When anti-IgE monoclonal antibody treatment is considered
  • Allergy tests: may determine allergic triggers and help provide allergen avoidance measures
  • Alpha-1 antitrypsin level: detects alpha-1 antitrypsin deficiency (for patients with persistent airway obstruction)
  • Biomarkers:
    • Sputum eosinophils: can be used as biomarker for T2-high asthma
    • Periostin: biomarker for eosinophilic inflammation despite use of corticosteroids
  • Sweat chloride test:
    • In children with persistent respiratory symptoms, to rule out cystic fibrosis
    • Low threshold in performing test due to lifelong implications of disease
  • Arterial blood gas (in severe asthma exacerbation):
    • Obtain when oxygen saturation of < 94%, no bronchodilator response, mental status change(s)
    • Initial finding(s): hypoxia (reduced oxygen), hypocarbia (due to hyperventilation), ↑ pH
    • Respiratory failure: hypoxia, hypercarbia, ↓ pH (respiratory acidosis)
Asthma flow volume

Flow-volume loop (blue line) showing an obstructive pattern of expiration, reduced peak expiratory flow (approximately 4 L/sec), and lung hyperinflation (approximately 4 L at residual volume and > 8 L after full inspiration). A normal pattern (green line) and restrictive pattern (red line) are shown for comparison.

Image by Lecturio.

Management

Non-pharmacologic management

  • Patient education: 
    • Asthma symptoms
    • Indications for and proper technique of bronchodilator and corticosteroid inhaler use
    • Discuss asthma action plan (PEF monitoring and corresponding action)
  • Goals: 
    • Control of symptoms and triggers
    • Reduce future risks and complications
  • Smoking cessation
  • Update influenza and pneumococcal vaccinations.

Pharmacologic and invasive management

  • For rescue treatment of acute exacerbation:
    • Short-acting beta2-agonists (SABA): for exercise-induced asthma or asthma exacerbation
    • Long-acting beta2-agonists (LABA): low-dose inhaled corticosteroids; formoterol can be used as acute symptom reliever (Global Initiative for Asthma guidelines)
  • Controllers:
    • Inhaled corticosteroids (ICS): most effective anti-inflammatory medications for asthma
    • Systemic corticosteroids:
      • Short-term treatment (< 7 days) recommended
      • Tapering required if > 2 weeks 
    • Leukotriene receptor antagonists (LTRA) and 5-lipoxygenase inhibitor:
      • Exercised-induced bronchospasm
      • Mild persistent asthma + allergic rhinitis
      • Asthma + aspirin-exacerbated respiratory disease
  • Monoclonal antibodies for severe asthma:
    • Anti-IgE or IgE antibody: omalizumab
    • IL-5 antagonist: mepolizumab, reslizumab 
    • IL-5 receptor antagonist: benralizumab
    • Anti-IL-4 receptor antagonist: dupilumab 
  • Bronchial thermoplasty: 
    • Ablates bronchial smooth muscles through the application of heat during bronchoscopy 
    • Carries procedure-related risks; only modest improvement of asthma
    • Strict criteria for selection (including patients who are unresponsive to maximum pharmacologic therapy)

Emergency management

Emergency management is for severe asthma exacerbation, not for responding to initial outpatient management.

  • Oxygen therapy goal: 93%–95% oxygen saturation (adults)
  • Inhaled therapy:
    • High dose of SABA via nebulizer or spacer
    • Nebulized ipratropium if no response to beta2-agonists
    • High-dose ICS given in 1st hour
  • Intravenous medication(s):
    • IV corticosteroids:
      • If asthma does not improve consistently after SABA treatment
      • If exacerbation occurs despite ongoing daily oral steroid therapy 
      • If exacerbation is recurrent after recent discontinuation of systemic steroids
    • Consider IV magnesium sulfate (1 dose):
      • Found to reduce hospital admissions in some patients
      • Not for routine use in asthma exacerbations
      • Contraindicated in renal insufficiency
  • Endotracheal intubation and mechanical ventilation in case of impending respiratory failure: 
    • Mental status changes (confused, agitated, or drowsy)
    • Silent chest on auscultation
    • Respiratory fatigue (respiratory rate > 30/min, heart rate > 120/min, use of accessory muscles)
    • Respiratory acidosis with increasing hypercapnia
    • Low oxygen saturation (< 92%) despite high-flow oxygen
  • Improved PEF > 80% and resolution of symptoms: discharge

Related videos

Management Guidelines

National Asthma Education and Prevention Program (NAEPP)

  • Basis of disease severity: 
    • Symptoms, activity limitation, SABA use, lung function
    • Includes spirometric values in determining severity (intermittent to persistent asthma)
    • Stepwise approach in initiation and continuation of medication(s) based on severity 
  • SABA: 1st-line therapy for acute exacerbation
  • Corticosteroids: 
    • Initiated in persistent asthma symptoms
    • Dose increased depending on severity
Table: NAEPP recommendations by classification
IntermittentPersistent: mildPersistent: moderatePersistent: severe
ControllerPreferred: daily low-dose ICSDaily low-dose ICS-LABADaily medium-dose ICS-LABA +/- LTRA, zileuton
Alternative controllers and additional therapiesDaily LTRADaily medium-dose ICS or daily low-dose ICS + LTRAMore severe symptoms: daily high-dose ICS-LABA +/- omalizumab +/- oral CS
RelieverSABA, as neededSABA, as neededSABA, as needed

Global Initiative for Asthma (GINA)

  • Updated 2020
  • Basis of severity: level of treatment (steps) needed to control symptoms and exacerbations
  • All patients given ICS either daily or as needed
  • ICS-formoterol:
    • 1st-line therapy (reliever) for adults and adolescents > 12 years of age
    • Preferred over SABAs for as-needed relief (except for age < 5 years)
Table: GINA 2019 recommendations by classification
Step 1 (< 2x a month)Step 2 (< 2x a month, not daily)Step 3 (most days)Step 4 (uncontrolled asthma)
ControllerSee preferred relieverLow-dose ICS-formoterol as needed or daily low-dose ICSDaily low-dose ICS-LABA
  • Step 4: daily medium-dose ICS-LABA
  • Step 5: daily high-dose ICS-LABA
Alternative controllerSee alternative relieverLow-dose ICS, if SABA is taken, or daily LTRADaily medium-dose ICS or daily low-dose ICS with LTRA
  • Daily high-dose ICS
  • More severe symptoms: Add-on tiotropium, LTRA, oral steroids, and other therapy (e.g., zileuton, anti–Ig-E/IL-5/IL-5R/IL-4)
Preferred relieverLow-dose ICS-formoterol, as neededLow-dose ICS-formoterol, as neededLow-dose ICS-formoterol, as neededLow-dose ICS-formoterol, as needed
Alternative relieverSABA, as neededSABA, as neededSABA, as neededSABA, as needed

Differential Diagnosis

  • Upper airway obstruction by tumor or laryngeal edema: causes stridor rather than wheezing. Flow-volume loop shows a limitation in flow in both inspiratory and expiratory curves. Bronchoscopy confirms diagnosis.
  • Foreign-body aspiration: shows localized or generalized wheezing. Chest X-ray can be normal or with unilateral hyperinflation or infiltrate. Bronchoscopy is diagnostic and therapeutic (foreign body retrieval).
  • Left ventricular failure: wheezing is accompanied by crackles. History, physical examination with chest X-ray, echocardiogram, and ECG help distinguish congestive heart failure.
  • Vocal cord dysfunction: presents with wheezing, cough, and dyspnea. Spirometry would show flattened inspiratory flow loop suggestive of variable extrathoracic obstruction. Laryngoscopy (gold standard) is recommended for diagnosis.
  • Eosinophilic granulomatosis with polyangiitis: may present with cough and wheezing. The condition is refractory to usual asthma treatment and has peripheral manifestations of vasculitis.
  • Chronic obstructive pulmonary disease (COPD): manifests with dyspnea, cough, and wheezing. The condition has a strong association with smoking history. Pulmonary function test will show obstructive pattern without significant reversibility. Emphysema, a form of COPD, also has reduced diffusing capacity of the lung for carbon monoxide (DLCO).

References

  1. Barnes P.J. (2018). Asthma. Jameson J, & Fauci A.S., & Kasper D.L., & Hauser S.L., & Longo D.L., & Loscalzo J. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. 
  2. Bell, M., Busse, W. (2015). The biology of asthma. Grippi, M., Elias, J., Fishman, J., Kotloff, R., Pack, A., Senior, R., Siegel, M. Fishman’s Pulmonary Diseases and disorders (5th Ed). McGraw-Hill.
  3. Carr, T., Zeki, A., Kraft, M. (2018). Eosinophilic and Noneosinophilic Asthma. Am J Respir Crit Care Med 197 (1): 22–37. https://www.atsjournals.org/doi/pdf/10.1164/rccm.201611-2232PP
  4. Esteban-Gorgojo, I., Antolin-Amerigo, D., Dominguez-Ortega, J., Quirce, S. (2018). Non-eosinophilic asthma: current perspectives. J Asthma Allergy. 11: 267–281. doi: 10.2147/JAA.S153097
  5. Fanta, C., Wood, R., Bochner, B., Hollingsworth, H., TePas, E. (Eds.). (2020). An overview of asthma management. UpToDate. Retrieved 28 Oct 2020, from https://www.uptodate.com/contents/an-overview-of-asthma-management
  6. Fanta, C., Barnes, P., Bochner, B., Hollingsworth H. (2020). Asthma in adolescents and adults: Evaluation and diagnosis. UpToDate. Retrieved 7 Sept 2020, from https://www.uptodate.com/contents/asthma-in-adolescents-and-adults-evaluation-and-diagnosis
  7. Kuruvilla, M., Eun-Hyung Lee, F.,  Lee, G. (2019). Understanding asthma phenotypes, endotypes and mechanisms of disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411459/
  8. National Asthma Education and Prevention Program: Expert Panel Report III: Guidelines for the diagnosis and management of asthma. Bethesda, MD. National Heart, Lung, and Blood Institute, 2007. (NIH publication no. 08-4051). www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm
  9. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. (2020). Retrieved 28 Oct 2020, from www.ginasthma.org
  10. Morris, M., Pearson, D., Mosenifar, Z. (Ed.). (2019) Asthma. Medscape. Retrieved 6 Sept 2020, from https://emedicine.medscape.com/article/296301-overview
  11. Sinyor, B., Perez, L. (2020) Pathophysiology of Asthma. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK551579
  12. Sze, E., Bhalla, A., Nair, P. (2019). Mechanisms and therapeutic strategies for Non-T2 asthma. European Journal of Allergy and Clinical Immunology. https://doi.org/10.1111/all.13985

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