Asthma and Severe Asthma

The answer first

Asthma is a heterogeneous inflammatory disease of the airways defined by a history of variable respiratory symptoms (wheeze, shortness of breath, chest tightness, cough) that fluctuate in time and intensity, together with variable expiratory airflow limitation. Two facts must land before anything else: [1]

1. Every patient with asthma needs an inhaled corticosteroid (ICS)-containing regimen. Since 2019, GINA has abolished short-acting beta-agonist (SABA) monotherapy — it does not suppress the underlying inflammation and it costs lives. The minimum therapy is as-needed low-dose ICS-formoterol (an anti-inflammatory reliever); most patients need regular daily ICS or ICS-LABA.
2. Severe asthma is rare. Roughly 3-8% of adults with asthma have severe disease — yet most patients labelled "severe" in clinic actually have uncontrolled asthma driven by non-adherence, poor inhaler technique, untreated comorbidities or an alternative diagnosis. The first job when a patient is referred for "severe asthma" is to prove the diagnosis, exclude mimics, and fix the basics before reaching for a biologic. [1]

The condition sits on a Type 2 (T2) inflammation axis in most patients: an eosinophilic, IgE-mediated, corticosteroid-responsive pathway driven by interleukin (IL)-4, IL-5 and IL-13. A minority have non-eosinophilic (neutrophilic) disease that responds poorly to steroids and is managed very differently. Phenotyping — by blood eosinophils and fractional exhaled nitric oxide (FeNO) — is now central to choosing between a biologic and predicting the response. [1]

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Pathophysiology

Asthma is not one disease. The airway abnormalities you can see — bronchoconstriction, mucous plugging, airway wall oedema and inflammation — are the final common pathway of at least two immunologically distinct processes. The dominant one, and the one that responds to steroids and biologics, is T2-high (eosinophilic) inflammation. [1]

The T2-high eosinophilic pathway

An inhaled allergen or other trigger is taken up by airway dendritic cells, which present antigen to naïve T-cells and drive their differentiation into Th2 cells. In parallel, type 2 innate lymphoid cells (ILC2s) in the airway epithelium respond directly to epithelial "alarmins" (TSLP, IL-25, IL-33) released by epithelial damage. Both Th2 cells and ILC2s produce the three cardinal Type 2 cytokines: [1]

• IL-4 drives B-cell class switching to IgE production and upregulates vascular cell adhesion molecules.
• IL-5 is the master regulator of eosinophil maturation, activation and survival. Eosinophils then infiltrate the airway wall and release major basic protein, eosinophil cationic protein and leukotrienes, which damage the epithelium and amplify bronchoconstriction.
• IL-13 drives goblet-cell metaplasia and mucus hypersecretion, upregulates inducible nitric oxide synthase (the source of measurable FeNO), and produces airway hyperresponsiveness. [1]

Allergen-specific IgE then binds high-affinity Fc-epsilon receptors on mast cells and basophils. Re-exposure to allergen cross-links IgE and triggers explosive mast-cell degranulation — the early-phase asthmatic response (minutes). The late-phase response (4-8 hours) is driven by recruited eosinophils and Th2 cells and is the target of ICS. [1]

Why this matters clinically: each cytokine maps to a drug target. IL-4/13 → dupilumab (anti-IL-4R alpha). IL-5 → mepolizumab and reslizumab (anti-IL-5), benralizumab (anti-IL-5 receptor alpha, depleting eosinophils by antibody-dependent cellular cytotoxicity). IgE → omalizumab. FeNO (an IL-13 read-out) and blood eosinophils (an IL-5 read-out) are the bedside biomarkers that select the right biologic. [1]

Airway remodelling

Chronic, undertreated T2 inflammation drives structural change in the airway wall: thickening of the subepithelial basement membrane (reticular layer, from collagen deposition), hypertrophy and hyperplasia of airway smooth muscle, goblet-cell hyperplasia, and mucosal angiogenesis. Remodelling narrows the calibre of the airway at rest and contributes to the fixed (non-reversible) component of airflow obstruction seen in long-standing or severe asthma. It explains why some patients never fully normalise their FEV1 — and why early, consistent ICS matters. [1]

Non-eosinophilic (T2-low) asthma

A minority of patients — perhaps 20-30% of severe asthmatics — have a pauci-eosinophilic, often neutrophilic phenotype. This is driven by Th17 cells and IL-8, with neutrophilic infiltration, and is associated with obesity, smoking, bacterial/viral infection and older age. It responds poorly to corticosteroids, which is a critical clinical point: escalating ICS in a neutrophilic asthmatic brings only side-effects. Management focuses on optimising non-T2 controllers (bronchodilators, smoking cessation, weight loss) and treating comorbidities rather than chasing a steroid response. [1]

DWE high-yield: The eosinophil/FeNO profile is the single most useful bedside test before stepping up therapy. A patient with blood eosinophils at least 300/microL and FeNO at least 50 ppb on high-dose ICS has T2-high severe asthma and is a candidate for a biologic. A patient with low eosinophils and low FeNO despite poor control should prompt a search for non-adherence, comorbidity and alternative diagnoses before any escalation. [1]

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Diagnosis

Asthma is a clinical diagnosis confirmed by objective lung function testing. The diagnosis is made when a patient with compatible symptoms demonstrates variable expiratory airflow limitation — that is, the obstruction comes and goes, and is at least partially reversible. [1]

Spirometry — the confirmatory test

Spirometry is the cornerstone. The key measurements are FEV1 (forced expiratory volume in 1 second), FVC (forced vital capacity) and the FEV1/FVC ratio. [1]

• In asthma, the FEV1/FVC ratio is reduced (obstructive pattern) — classically below the lower limit of normal (LLN), or below 0.75-0.80.
• Bronchodilator reversibility is the diagnostic signature: after 400 mcg of inhaled salbutamol, an increase in FEV1 of at least 12% AND at least 200 mL supports asthma. A larger response (e.g. more than 400 mL) is more specific. [1]

DWE trap: A normal spirometry result does not exclude asthma, because airflow obstruction is variable by definition. If spirometry is normal but suspicion is high, the next step is bronchoprovocation testing (methacholine or mannitol challenge) — a negative test has a high negative predictive value and effectively excludes active asthma — or peak flow monitoring over time to capture variability. [1]

Peak expiratory flow variability

When spirometry is normal, serial peak expiratory flow (PEF) monitoring over at least 2 weeks captures the variability that defines asthma: [1]

• Diurnal variability more than 10% (calculated as the daily maximum minus minimum, divided by the mean) over 2 weeks supports the diagnosis.
• A morning dip pattern (low morning PEF recovering through the day) is characteristic.
• PEF is effort-dependent and less reliable than spirometry — use it as supportive evidence, not a standalone test. [1]

FeNO — the T2 inflammation biomarker

Fractional exhaled nitric oxide is a non-invasive surrogate for IL-13-driven Type 2 airway inflammation: [1]

• FeNO at least 50 ppb in an adult (at least 35 ppb in a child) supports a diagnosis of asthma and predicts a good response to ICS.
• A low FeNO (less than 25 ppb) in a symptomatic patient on no ICS argues against T2-high asthma and should prompt a search for alternative diagnoses (vocal cord dysfunction, GERD).
• FeNO is also used to guide ICS stepping and to detect non-adherence: a patient on high-dose ICS who nonetheless has a high FeNO is almost certainly not taking their inhaler. [1]

Other investigations

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The GINA stepwise approach

GINA classifies treatment in two "tracks" — Track 1 (preferred) uses low-dose ICS-formoterol as both reliever and (at higher steps) maintenance; Track 2 uses a separate SABA reliever with an ICS-containing maintenance regimen. Track 1 is preferred because the as-needed ICS-formoterol delivers anti-inflammatory cover at the moment symptoms spike, reducing severe exacerbations. [1]

The central principle is that every patient carries an ICS in their reliever or maintenance regimen. A SABA-only inhaler is no longer acceptable at any step. [1]

Step 1 — As-needed low-dose ICS-formoterol

For patients with symptoms less than twice a month and no risk factors (no severe exacerbation in the prior year, no nocturnal waking): as-needed low-dose budesonide-formoterol (e.g. Symbicort 200/6 Turbuhaler, one inhalation as needed). The Novel START trial (Beasley 2019) showed as-needed budesonide-formoterol was superior to as-needed SABA alone for preventing severe exacerbations in mild asthma. [1]

Step 2 — Regular low-dose ICS OR as-needed ICS-formoterol

For symptoms 2 or more days per week, or nocturnal waking: regular daily low-dose ICS (e.g. budesonide 400 mcg/day, fluticasone propionate 100 mcg twice daily) as maintenance. As-needed low-dose ICS-formoterol is an equally acceptable alternative and may be preferred for adherence. [1]

Examiner point — why GINA killed SABA monotherapy: The Salmeterol Multicenter Asthma Research Trial (SMART, 2006) and registries showed that SABA-only treatment — particularly when overused — was associated with an excess of asthma deaths, because the patient feels relief while the underlying inflammation burns unchecked. A patient using a SABA more than two canisters per year is at markedly increased risk of a severe exacerbation. Every DWE answer on "mild asthma" must now recommend an ICS-containing regimen. [1]

Step 3 — Low-dose ICS-LABA (or MART)

For symptoms uncontrolled on low-dose ICS alone: step up to low-dose ICS-LABA (e.g. budesonide-formoterol 200/6 one inhalation twice daily, fluticasone-salmeterol). In the preferred Track 1, this is delivered as MART (maintenance and reliever therapy) — the patient takes a fixed maintenance dose AND uses the same ICS-formoterol inhaler as the reliever up to a daily maximum. MART reduces severe exacerbations compared with fixed-dose ICS-LABA plus a separate SABA. [1]

Step 4 — Medium-dose ICS-LABA (± LAMA)

If still uncontrolled: increase to medium-dose ICS-LABA. At this step consider adding a long-acting muscarinic antagonist (LAMA) — tiotropium 5 mcg (2.5 mcg in ANZ brand) once daily via Respimat. Kerstjens (2012) showed tiotropium added to ICS-LABA improved FEV1 and reduced exacerbations in uncontrolled asthma, and it became the first Step 4/5 add-on option before a biologic. [1]

Step 5 — High-dose ICS-LABA + LAMA, refer for severe asthma, add biologic / oral corticosteroid

For patients still uncontrolled on high-dose ICS-LABA ± LAMA: refer to a severe asthma service for phenotyping and biologic therapy (see below). Low-dose oral corticosteroids (e.g. prednisolone 5-10 mg daily) are a last resort because of cumulative toxicity — osteoporosis, diabetes, adrenal suppression, cataracts, skin thinning and infection risk — and should only be used after biologics have failed or are unsuitable, with bone and glucose protection. [1]

Stepping down

When asthma has been well controlled for at least 3 months, step down to the lowest effective regimen. Reduce the ICS dose by 25-50% at a time, monitor symptoms and PEF, and never stop ICS abruptly (rebound exacerbation). Document the step-down and give the patient an action plan for what to do if symptoms recur. [1]

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Severe asthma — definition and referral

Severe asthma (ERS/ATS 2014 definition) is asthma that requires high-dose ICS (or a second controller, e.g. LABA/LAMA/biologic) or systemic corticosteroids to prevent it from becoming uncontrolled — or that remains uncontrolled despite this therapy. The critical distinction is from difficult-to-treat asthma, which is uncontrolled due to modifiable factors: poor adherence, incorrect technique, untreated comorbidities, ongoing exposure (smoking, allergen) or an alternative diagnosis. [1]

Before any patient is labelled severe: [1]

1. Confirm the diagnosis — objective variable airflow limitation; exclude COPD (partially reversible vs fully reversible), vocal cord dysfunction, allergic bronchopulmonary aspergillosis, bronchiectasis, cardiac failure.
2. Check adherence and technique — prescription refill data, observed technique, FeNO suppression test (FeNO rises after directly-observed ICS for 2 weeks confirms non-adherence).
3. Treat comorbidities — allergic rhinitis, chronic rhinosinusitis/nasal polyps, GERD, obesity, obstructive sleep apnoea, anxiety/depression, vocal cord dysfunction.
4. Phenotype — blood eosinophils and FeNO (ideally on and off steroids) to identify the T2-high group suitable for a biologic. [1]

DCE long-case trap: The single most common error in a "severe asthma" long case is reaching for a biologic before completing this workup. A patient referred for "severe, steroid-resistant asthma" who turns out to have vocal cord dysfunction with a normal FeNO and normal spirometry variability does not have severe asthma at all — and no escalation of therapy will help. Always ask: "What evidence confirms this is asthma, and what comorbidities have you treated?" [1]

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Biologics for severe asthma

Four biologics dominate adult severe asthma practice. Selection is phenotype-driven: [1]

Choosing a biologic

The decision rests on three questions: [1]

1. Is it T2-high? Blood eosinophils at least 300/microL or FeNO at least 25 ppb (ideally both) on high-dose ICS-LABA identify the responder group. If neither is elevated, current biologics are unlikely to help — re-evaluate the diagnosis and comorbidities.
2. Is there an atopic / allergic driver? If yes (sensitisation, elevated IgE, perennial allergen exposure), omalizumab is an option; it is also useful in patients with coexisting chronic spontaneous urticaria.
3. Is the patient oral-steroid-dependent? Both dupilumab (VENTURE) and benralizumab (ZONDA) have demonstrated oral-corticosteroid-sparing benefit — a major advantage given the cumulative toxicity of maintenance prednisolone. [1]

In practice, dupilumab has become first-line for many T2-high severe asthmatics because it targets both the IL-13 (FeNO) and IL-5 (eosinophil) arms of the T2 pathway, has a dual oral-steroid-sparing claim, and also treats coexisting atopic dermatitis and chronic rhinosinusitis with nasal polyps. An anti-IL-5 (mepolizumab or benralizumab) is preferred when eosinophils are very high and the patient has no concomitant skin disease. Omalizumab is reserved for clearly allergic phenotypes within the IgE/weight dosing window. [1]

Monitoring a biologic

• Trial for 3-4 months before judging response, using exacerbation rate, oral corticosteroid requirement, FEV1, the Asthma Control Questionnaire (ACQ-5) and the Asthma Quality of Life Questionnaire (AQLQ).
• A clinically meaningful response is typically a at least 50% reduction in exacerbations and/or a meaningful steroid reduction. If there is no response after 4 doses, withdraw and reconsider the phenotype.
• Continue background controller therapy; taper oral corticosteroid once stable. Do not discontinue a biologic abruptly in a steroid-dependent patient without a taper plan. [1]

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Acute severe asthma — emergency management

Acute asthma is a medical emergency graded by severity, because the severity dictates where the patient is managed and how aggressively. The standard is the BTS/Asthma UK criteria, which ANZ and UK practice share. [1]

Severity grading (BTS / Asthma UK)

The pre-arrest sign you must not miss: In a tiring asthmatic, the PaCO2 rises into the normal range (4.6-6.0 kPa, 35-45 mmHg). A "normal" CO2 in a patient who is working hard to breathe is abnormal — it means they are failing to ventilate and is a life-threatening sign. A falling heart rate (bradycardia), a silent chest (no wheeze because airflow is too low to generate sound) and exhaustion are the final pre-arrest triad — call ICU immediately. [1]

Immediate management (first 15-30 minutes)

1. Assess ABC and severity — RR, HR, BP, SpO2, ability to speak, use of accessory muscles, chest auscultation. Put the patient on a cardiac monitor.
2. Oxygen — high-flow oxygen via mask to target SpO2 93-95%. In asthma there is no risk of CO2 retention from oxygen (that is a COPD concern), so do not titrate low — give enough.
3. Nebulised salbutamol — 5 mg salbutamol (2.5 mg in the ANZ paediatric or frail-elderly brand) driven by oxygen (6-8 L/min), repeated every 15-20 minutes (up to 3 doses in the first hour, then continuous if severe). Driving the nebuliser with oxygen (not air) prevents worsening hypoxia in the severely obstructed patient. [1]4. Nebulised ipratropium bromide — 500 mcg added to each of the first three salbutamol nebulisers (the combination is more effective than salbutamol alone in severe attacks). Ipratropium is a muscarinic antagonist providing complementary bronchodilation.
4. Systemic corticosteroid — prednisolone 40-50 mg orally (if able to take it) OR hydrocortisone 100 mg IV (or 200 mg IV) if severe or vomiting. Steroids take 4-6 hours to work; give them early and do not wait. Oral and IV are equivalent in efficacy.
5. IV magnesium sulfate — for acute severe asthma that has not responded adequately to initial nebulised bronchodilators and steroids: 1.2-2 g magnesium sulfate IV over 20 minutes. The Cochrane review (Kew 2014) showed a 25% reduction in hospital admissions (NNT 7) in adults. Monitor for flushing, hypotension and areflexia. [1]

Escalation — when first-line therapy fails

If the patient is life-threatening or failing to improve after the first hour: [1]

• High-dose nebulised salbutamol continuously (e.g. 5-10 mg/hour).
• Repeat IV magnesium (with monitoring) — some protocols allow a second dose.
• IV salbutamol infusion — 250 mcg IV bolus then an infusion (e.g. 3-20 mcg/min), with cardiac monitoring. Evidence is weak and it carries a risk of tachyarrhythmia, lactic acidosis and hypokalaemia; it is a second-line agent when inhaled delivery is impossible or insufficient.
• IV aminophylline / theophylline — loading dose 5 mg/kg over 20 minutes then infusion. Rarely used; narrow therapeutic window and arrhythmia risk. Consider only when other measures fail.
• Heliox (helium-oxygen mixture) reduces work of breathing; evidence is limited — a temporising measure in severe obstruction, not a definitive therapy. [1]

NIV and intubation

Non-invasive ventilation (NIV / BiPAP) in acute asthma is controversial and not routinely recommended. It may reduce work of breathing in selected cooperative patients with hypercapnia, but risks dynamic hyperinflation and delayed intubation. Use only in an ICU setting by experienced staff, and never as a substitute for intubation in a patient meeting life-threatening criteria. [1]

Intubation criteria — any one of:

• Deteriorating consciousness, exhaustion, or apnoea.
• PaCO2 rising despite maximal medical therapy (the patient is fatiguing).
• Silent chest with failing respiratory effort.
• Cardiac arrest or peri-arrest (bradycardia, severe hypoxia). [1]

Intubation of a severe asthmatic is high-risk: ketamine is the preferred induction agent (bronchodilator, maintains blood pressure); ventilate slowly with a long expiratory time to avoid breath-stacking and dynamic hyperinflation (permissive hypercapnia). Have anaesthetics/ICU involved early, before the patient arrests. [1]

Discharge planning

Discharge only when:

• The patient is clinically stable on inhaled therapy (no longer needing nebulisers; on their discharge controller regimen).
• PEF is at least 75% of best/predicted and stable for at least 4 hours post last bronchodilator. [1]

The discharge bundle that prevents readmission (every patient, every time):

1. Continue oral prednisolone 40-50 mg for 5 days (longer if slow recovery; do not taper a short course). [1]2. Optimise the inhaled controller — ensure the patient is on ICS-containing therapy at an appropriate dose (this is the teachable moment: they had a severe attack, so step up).
2. Written asthma action plan — traffic-light zones with PEF or symptom thresholds and an oral corticosteroid starter pack.
3. Check inhaler technique — observe the patient using their device; correct errors; consider a spacer for MDI users.
4. Follow-up — review within 48 hours (primary care or rapid-access) and in a respiratory clinic within 4 weeks to reassess control and step down. [1]

DWE discriminator: Patients admitted with acute asthma have a markedly elevated risk of further severe attacks and death in the following year. An asthma admission is a sentinel event — it mandates a review of the maintenance regimen, an action plan, and structured follow-up. The single most evidence-based readmission-prevention intervention is ensuring the patient leaves on ICS-containing therapy with a written action plan. [1]

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Asthma action plans and inhaler technique

Written asthma action plans

Every patient with asthma — particularly after a severe attack — should leave with a written, personalised action plan. The plan has three or four zones (traffic-light model): [1]

• Green (well): take regular maintenance therapy; PEF above 80% of best.
• Yellow (caution / worsening): increase reliever use; start oral corticosteroids (e.g. prednisolone 40-50 mg daily); step up ICS (quadruple the dose if on a single inhaler, or add a separate course). PEF 50-80% of best.
• Red (emergency): call an ambulance; continue reliever; PEF below 50% of best or rapidly falling; features of life-threatening attack. [1]

PEF-based plans outperform symptom-based plans in patients with poor symptom perception (a feature of fatal/near-fatal asthma). Give the patient a peak flow meter and their best-ever value, and supply an oral corticosteroid starter pack for high-risk patients. [1]

Inhaler technique

Poor inhaler technique is the commonest cause of uncontrolled asthma — and it is universal in long-case patients. Assess it at every visit by watching the patient use their device, not by asking if they know how. Common errors: failure to exhale before inhalation, no breath-hold, not shaking an MDI, failure to use a spacer with an MDI, and priming errors with dry-powder inhalers. [1]

Device principles:

• Pressurised MDI (pMDI): slow, deep inhalation with breath-hold; always use a spacer — it improves deposition, reduces oropharyngeal deposition (and therefore candidiasis/dysphonia) and is essential in acute attacks.
• Dry-powder inhaler (DPI, e.g. Turbuhaler, Accuhaler): requires a fast, forceful inhalation; sensitive to moisture (keep dry).
• Soft-mist inhaler (Respimat): slow, deep inhalation; used for tiotropium in asthma. [1]

ICS-specific adverse effects — oral candidiasis (thrush) and dysphonia (hoarse voice) — are reduced by rinsing the mouth after each ICS dose and by spacer use. High-dose ICS over years carries a small risk of adrenal suppression and reduced bone mineral density; bone protection (vitamin D, calcium, DEXA, a bisphosphonate if needed) is part of severe-asthma care. [1]

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How this is examined

DWE MCQ targets the highest-yield facts: (1) GINA abolished SABA monotherapy — the correct "mild asthma" answer is as-needed ICS-formoterol; (2) reversibility criteria (at least 12% and 200 mL in FEV1); (3) life-threatening features and the pre-arrest meaning of a "normal" PaCO2; (4) IV magnesium dose (1.2-2 g over 20 min) and its role; (5) biologic selection by phenotype (eosinophils/FeNO for dupilumab and anti-IL-5; IgE for omalizumab). [1]

DCE long case rewards a candidate who, given a "severe asthma" patient, does not leap to a biologic but first confirms the diagnosis, excludes mimics (ABPA, vocal cord dysfunction, COPD), checks adherence and technique, treats comorbidities (rhinitis, OSA, obesity, GERD), and only then phenotypes for a biologic — articulating the oral-steroid-sparing benefit and the monitoring plan. [1]

DCE short case rewards a candidate who examines the respiratory system systematically, states that a well-controlled asthmatic may have a normal examination (the absence of signs is itself a key point), and — in an acute scenario — names the life-threatening features and the correct immediate sequence (oxygen, salbutamol + ipratropium nebulised, systemic steroid, IV magnesium, escalate). [1]

High-yield exam discriminators

1. As-needed ICS-formoterol (not SABA) is the minimum therapy for mild asthma since GINA 2019. Any answer recommending SABA monotherapy is wrong.
2. A "normal" PaCO2 in a tiring asthmatic is life-threatening, not reassuring — the patient is failing to ventilate.
3. Silent chest, exhaustion, bradycardia and cyanosis = imminent arrest — call ICU, prepare for intubation.
4. High FeNO and high eosinophils despite high-dose ICS = non-adherence until proven otherwise (run a directly-observed ICS trial).
5. Dupilumab and benralizumab are oral-steroid-sparing — choose them when maintenance prednisolone is the problem.
6. The single most effective readmission-prevention intervention is an ICS-containing regimen plus a written asthma action plan at discharge. [1]

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Sources and regional anchoring

GINA Global Strategy for Asthma Management and Prevention (2024); BTS/SIGN British Guideline on the Management of Asthma (SIGN 158, 2019); NICE NG80; National Asthma Council Australia — Australian Asthma Handbook (TSANZ-endorsed); ERS/ATS Severe Asthma Guidelines (2014). Drug doses follow ANZ brands and the Australian Asthma Handbook as primary, with UK/US deltas noted where they differ (e.g. ANZ nebulised salbutumol dosing; omalizumab IgE/weight dosing tables shared across regions). [1]

References

1. [1]Beasley R, Holliday M, Reddel HK, et al. Controlled Trial of Budesonide-Formoterol as Needed for Mild Asthma N Engl J Med, 2019.PMID 31112386
2. [2]Kerstjens HAM, Disse B, Schröder-Babo W, et al. Tiotropium in asthma poorly controlled with standard combination therapy N Engl J Med, 2012.PMID 22938706
3. [3]Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE Allergy, 2005.PMID 15679715
4. [4]Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial Lancet, 2012.PMID 22901886
5. [5]Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma N Engl J Med, 2014.PMID 25199059
6. [6]Bleecker ER, FitzGerald JM, Chanez P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β(2)-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial Lancet, 2016.PMID 27609408
7. [7]Nair P, Wenzel S, Rabe KF, et al. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma N Engl J Med, 2017.PMID 28530840
8. [8]Castro M, Corren J, Pavord ID, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma N Engl J Med, 2018.PMID 29782217
9. [9]Rabe KF, Nair P, Brusselle G, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma N Engl J Med, 2018.PMID 29782224
10. [10]Kew KM, Kirtchuk L, Michell CI Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department Cochrane Database Syst Rev, 2014.PMID 24865567