Asthma

Overview

• Chronic inflammatory airway disease with episodic, reversible obstruction: cough, wheezing, chest tightness, and dyspnea from airway inflammation and bronchial hyperreactivity, spanning phenotypes (allergic/type 2-high, cough-variant, exercise-induced, occupational, aspirin-exacerbated respiratory disease).
• Onset at any age: adult-onset disease is more often occupational or non-atopic and more sustained.
• Distinct from COPD by reversibility: unlike the largely fixed obstruction of chronic obstructive pulmonary disease (postbronchodilator FEV1/FVC <0.70), asthma's obstruction reverses with treatment.
• Routine exacerbations covered here; refractory or near-fatal attacks are a separate entity: see status asthmaticus.

Epidemiology

• Common, with real mortality: roughly 7.9% of the US population has diagnosed asthma (9.6 million office visits/year); 9.9 deaths per million Americans in 2017.
• Disproportionate impact: prevalence and mortality are higher among adults older than 65 years, women, Black persons, and persons below the poverty level.
• Childhood predominance: often linked to atopy and dust mite/cockroach exposure.
• Occupational contribution: 15% of adult asthma is work-related.

Risk factors

• Genetic predisposition to atopy and bronchial hyperreactivity, interacting with environmental exposures.
• Indoor and outdoor allergens: dust mites, furred animals, cockroaches, molds, pollens.
• Tobacco smoke exposure, active or secondhand.
• Occupational sensitizers: latex, grains, animal/plant allergens, and diisocyanates; farmers, health care workers, bakers, and polyurethane manufacturers are at particular risk.
• Viral respiratory infection, the most robust exacerbation trigger.
• Air pollution, indoor and outdoor.
• Obesity, raising incidence and worsening control.
• Aspirin/NSAID sensitivity, defining aspirin-exacerbated respiratory disease.

Pathophysiology

• Chronic airway inflammation is the central process: a variable infiltrate of eosinophils, T lymphocytes, mast cells, and neutrophils persists even between symptomatic episodes.
• Type 2 (Th2-driven) inflammation predominates in at least half of patients: Th2 cytokines raise eosinophils, IgE, and exhaled nitric oxide.
• Non-type-2 (neutrophilic) inflammation is more common in older adults, who respond less predictably to anti-inflammatory therapy.
• Structural airway remodeling compounds inflammation: edema, fibrosis, smooth muscle hypertrophy, and mucus hypersecretion.
• Bronchial hyperreactivity produces episodic smooth muscle constriction to stimuli harmless to a healthy airway, the diagnostic hallmark.

Clinical features

• Variable, intermittent symptoms define the clinical pattern: cough, wheezing, chest tightness, and dyspnea with identifiable triggers; variability plus objectively confirmed reversible obstruction (see Diagnosis) establishes the diagnosis.
• Diurnal variation, characteristically worse evening and early morning.
• Physical exam is often normal between episodes, though wheezing or a prolonged expiratory phase may be present during symptoms.
• Asthmatic triad: nasal polyps, aspirin sensitivity, and wheezing mark aspirin-exacerbated respiratory disease.
• Chronic cough as the sole manifestation defines cough-variant asthma, typically with normal spirometry, requiring bronchial hyperreactivity testing to confirm.
• Weekend/time-away improvement is a key indicator of occupational asthma.
• Exercise-triggered symptoms: exercise-induced bronchoconstriction is common in known asthma and can occur without asthma, typically in elite athletes exercising in cold, dry air.

Differential diagnosis

• COPD: fixed obstruction (postbronchodilator FEV1/FVC <0.70) that does not reverse with bronchodilator, unlike asthma; overlap exists in older patients.
• Vocal cord dysfunction: inspiratory, not expiratory, breathlessness with absent wheeze; laryngoscopy shows paradoxical cord adduction during an episode.
• Heart failure ("cardiac asthma"): dyspnea and wheezing from pulmonary edema, with orthopnea and elevated jugular venous pressure absent in uncomplicated asthma.
• Gastroesophageal reflux disease: cough and chest pain that respond to a proton pump inhibitor trial rather than bronchodilator.
• Chronic rhinosinusitis/upper airway cough syndrome: postnasal-drip cough lacks wheezing, though it often coexists with cough-variant asthma.
• Bronchiectasis: chronic productive cough with bronchial dilation on chest CT, not reversible spirometric obstruction.
• Allergic bronchopulmonary aspergillosis: difficult-to-control asthma plus elevated Aspergillus-specific IgE and central bronchiectasis, absent in uncomplicated asthma.
• Eosinophilic granulomatosis with polyangiitis: late-onset, difficult-to-treat asthma with chronic sinusitis, blood eosinophilia above 10% or 1500/uL, migratory infiltrates, and mononeuritis multiplex; ANCA (MPO) is positive in only 40% to 60%; see EGPA.
• Obstructive sleep apnea: snoring and witnessed apneas on polysomnography; worsens control but lacks asthma's variable airflow obstruction.
• Central airway obstruction (tumor, foreign body): fixed, often monophonic wheeze that does not vary with bronchodilator, unlike diffuse asthmatic wheeze.
• Anaphylaxis: acute bronchospasm plus urticaria or hypotension after an exposure; see anaphylaxis.

Diagnosis

• Confirmation of reversible airflow obstruction is the diagnostic basis of asthma: a postbronchodilator FEV1 increase of at least 12% and 200 mL from baseline confirms it; improvement after 4 weeks of anti-inflammatory treatment also supports it. Exacerbation severity is graded by respiratory rate, heart rate, ability to speak in sentences, and oxygen saturation (see Management).
• First, obtain spirometry (FEV1, FVC, FEV1/FVC) before and after bronchodilator to test for that reversibility.
• Then, if spirometry is normal or nondiagnostic, perform bronchial challenge testing, most commonly inhaled methacholine; a negative test effectively excludes asthma, while a positive test needs clinical correlation.
• For suspected exercise-induced bronchoconstriction with normal resting spirometry, perform an exercise or isocapnic hyperventilation challenge with cold, dry air: a fall in FEV1 of 15% or more from the prechallenge value is diagnostic, and proving hyperreactivity separates EIB from vocal cord dysfunction and cardiac mimics.
• For suspected occupational asthma, document the work relationship objectively: serial peak expiratory flow at work versus away from work (a decline of 20% or more at the workplace compared with home is diagnostic), or spirometry before and after workplace exposure; then classify the type:
  • Sensitizer-induced: IgE-mediated response to high-molecular-weight agents or diisocyanates (see Risk factors), developing gradually; once sensitized, very low exposures provoke symptoms.
  • Irritant-induced (reactive airways dysfunction syndrome): no prior asthma, a single high-level fume, gas, or vapor exposure, symptoms for at least 3 months afterward, confirmed by obstruction or hyperreactivity.
  • Work-exacerbated: preexisting asthma worsened by the same workplace factors.
• Next, consider fractional exhaled nitric oxide testing when the diagnosis remains uncertain or spirometry cannot be performed.
• Obtain a chest radiograph to exclude alternatives (COPD, heart failure, parenchymal disease, bronchiectasis), particularly in older adults.
• Assess atopy and phenotype with allergy skin testing or serum allergen-specific IgE, plus eosinophil count and total IgE, to identify a type 2-high phenotype relevant to biologic selection.
• Grade control before adjusting treatment with a validated tool (Asthma Control Test or Questionnaire); daytime symptoms fewer than 2 days/week and nocturnal symptoms fewer than 2 times/month define well-controlled disease.

Clinical pearl. A negative methacholine challenge in a symptomatic patient effectively rules out asthma; a positive test only confirms bronchial hyperreactivity and still needs clinical correlation, because other disorders can produce a positive result too.

Management

• First, give every patient quick-relief (rescue) therapy: albuterol metered-dose inhaler 2 puffs (90 mcg/puff) inhaled every 4-6 hours as needed; use of a short-acting beta-2 agonist (SABA) more than 2 days a week (excluding pre-exercise use) signals the need to step up.
• Then start stepwise controller therapy, escalating with symptom frequency (ICS = inhaled glucocorticoid, LABA = long-acting beta-2 agonist):
  • Step 1-2: as-needed budesonide-formoterol 1 puff as needed (off-label), or daily budesonide 200-400 mcg/day plus as-needed SABA.
  • Step 3: daily budesonide-formoterol 80/4.5-160/4.5 mcg 1 puff twice daily, used as both maintenance and as-needed reliever, up to a maximum 12 puffs (54 mcg formoterol)/day; or daily low-dose ICS-LABA plus as-needed SABA.
  • Step 4: daily budesonide-formoterol 160/4.5 mcg 2 puffs twice daily as maintenance and reliever; add montelukast 10 mg PO nightly for coexisting allergic rhinitis or aspirin sensitivity.
  • Step 5: daily high-dose ICS-LABA plus tiotropium 2.5 mcg x2 inhalations (5 mcg total) once daily and as-needed SABA; consult an asthma specialist at this step or higher.
  • Step 6: daily high-dose ICS-LABA plus prednisone 5-10 mg PO once daily and as-needed SABA (add a biologic per the next bullet if still uncontrolled).
• If moderate-to-severe asthma remains uncontrolled despite verified adherence and technique, add a phenotype-matched biologic:
  • Atopic (IgE-high): omalizumab 75-375 mg SC every 2-4 weeks, dosed by weight and IgE; reassess at 16 weeks.
  • Eosinophilic (blood eosinophils 150-400 cells/uL or higher): mepolizumab 100 mg SC every 4 weeks, or benralizumab 30 mg SC every 4 weeks x3 then every 8 weeks.
  • Severe type 2: dupilumab 400 mg SC once, then 200 mg SC every 2 weeks.
• For a mild-to-moderate exacerbation, escalate self-treatment: increase reliever frequency, increase controller dose, and add prednisone 40-50 mg PO once daily for 5-7 days, then stop without a taper.
• If the patient does not improve with self-care, or shows severe signs (unable to speak in full sentences, accessory muscle use, respiratory rate above 30/min, heart rate above 120/min, SpO2 below 90%, agitation, confusion, or drowsiness), evaluate in an acute care facility.
• In the acute care setting, treat in sequence:
  • Frequent inhaled SABA: albuterol 4-8 puffs or 2.5 mg nebulized every 20 minutes x3 in the first hour.
  • Add nebulized ipratropium 0.5 mg every 20 minutes x3, reducing hospital admission.
  • Give methylprednisolone 60-80 mg IV once then 40-60 mg IV/PO every 6-12 hours (or oral prednisone 40-50 mg daily if tolerating oral intake), continued 3-5 days moderate or 10-14 days severe.
  • Give oxygen to keep SpO2 above 93%.
• If refractory to this initial acute-care management, or the patient develops impending respiratory failure, escalate per status asthmaticus.
• Treat comorbidities at every step (reflux, allergic rhinitis, sleep apnea, obesity), as detailed under Prevention.
• Step down only after 3 months of good control; step up only after checking adherence, technique, and exposures first.
• For exercise-induced bronchoconstriction, give budesonide 200 mcg plus albuterol 2 puffs before exercise (or budesonide-formoterol 1 puff before exercise) instead of SABA alone, plus a preexercise warm-up.
• For occupational asthma, remove the patient from the sensitizer early and completely (workplace modification or reassignment) alongside stepwise therapy; with prolonged exposure, symptoms become persistent and remit only after long absence from work.
• For aspirin-exacerbated respiratory disease, add strict aspirin/NSAID avoidance and montelukast 10 mg PO nightly; refer for aspirin desensitization if refractory.
• For pregnant patients, continue standard therapy at the doses above, since control benefit outweighs fetal risk; monitor most closely in the second trimester.

Complications

• Respiratory failure during a severe exacerbation, the most immediately life-threatening complication.
• Irreversible (fixed) airway obstruction, in patients with severe, sustained, poorly controlled disease, blurring the distinction from COPD.
• Airway remodeling: repeated inflammation progressively reduces baseline lung function.
• Medication-related adverse effects: adrenal suppression, reduced bone density, and pneumonia with high-dose inhaled glucocorticoids; hyperglycemia, hypertension, weight gain, and infection with recurrent oral courses.
• Allergic bronchopulmonary aspergillosis in susceptible patients.

Prognosis

• Mortality is concentrated in identifiable high-risk patients: a near-fatal attack or prior intubation, an emergency/hospital visit within 12 months, poor adherence, recent oral glucocorticoid use, psychosocial stressors, food allergy, and SABA overuse each independently raise the risk of asthma-related death.
• Overall US mortality is low but real: 9.9 deaths per million Americans in 2017.
• Childhood asthma often improves with age, particularly in males; severe childhood disease more often persists into adulthood.

Prevention

• Screen for and treat comorbidities that worsen control: proton pump inhibitor trial for 2 months for suspected reflux; intranasal glucocorticoids for allergic rhinitis; polysomnography for suspected obstructive sleep apnea, with positive airway pressure if confirmed.
• Avoid identified triggers: allergen management (mold abatement, pest control, air filtration), tobacco avoidance, and removal from occupational exposures.
• Keep SABA use below 2 days per week; more frequent use prompts controller step-up.
• Target a normal BMI through diet, exercise, or bariatric surgery for eligible patients with obesity.
• Give every patient a written action plan with self-escalation thresholds (reliever frequency, controller dose, a 5-7 day prednisone burst) and when to seek care.
• Counsel strict aspirin/NSAID avoidance in aspirin-exacerbated respiratory disease; re-exposure can cause life-threatening bronchospasm within minutes to hours.
• Consider subcutaneous allergen immunotherapy at steps 2-4 for patients controlled through initiation, buildup, and maintenance.

Key points

• Asthma is defined by variable, reversible airflow obstruction: a postbronchodilator FEV1 increase of at least 12% and 200 mL, or a positive challenge when spirometry is normal.
• A negative methacholine challenge rules out asthma; a positive one only confirms hyperreactivity and needs clinical correlation.
• Inhaled glucocorticoids are the most effective controller class; use an ICS-containing regimen, not SABA alone, at every step.
• SABA use more than 2 days a week is the actionable threshold for stepping up therapy; single-agent LABA use is never appropriate because of increased asthma-related death risk.
• Biologic therapy (omalizumab, mepolizumab, benralizumab, dupilumab) is reserved for severe persistent asthma matched to phenotype after confirming adherence and inhaler technique.
• Acute exacerbations are treated with frequent SABA, ipratropium, systemic glucocorticoids, and oxygen to SpO2 above 93%; escalate refractory attacks per status asthmaticus.