8.1 Asthma: Diagnosis, Chronic Management & Acute Attacks

Obstructive airway diseases constitute one of the most heavily tested domains in MRCP(UK) Part 1. Candidates must demonstrate command of objective diagnostic cut-offs, evidence-based chronic escalation pathways (including Maintenance and Reliever Therapy [MART] and biologicals), the clinical distinction between acute severe and life-threatening asthma, and the physiological principles underpinning controlled oxygen and non-invasive ventilation in chronic obstructive pulmonary disease (COPD).

---

1. Asthma: Diagnostic Principles & Objective Testing (BTS/NICE/SIGN 2024)

Asthma is a heterogeneous disorder characterized by chronic airway inflammation, variable expiratory airflow limitation, and airway hyperresponsiveness. Clinical symptoms (wheeze, breathlessness, chest tightness, nocturnal cough) possess poor diagnostic specificity alone. UK practice is now governed by the joint BTS/NICE/SIGN asthma guideline published on 27 November 2024 (NICE NG245), which replaced NICE NG80 and the chronic-management sections of the 2019 BTS/SIGN guideline (SIGN 158). It strictly mandates objective physiological and biological confirmation before a diagnosis is made, and it sets FeNO and blood eosinophil count as the preferred first-line diagnostic tests in adults. Note that NG245 covers diagnosis, monitoring and chronic management only - acute attacks and severe asthma remain outside its scope and are covered by the separate BTS/SIGN acute asthma guidance used below.

Objective Diagnostic Criteria

• Fractional Exhaled Nitric Oxide (FeNO): Nitric oxide is produced by inducible nitric oxide synthase (iNOS) upregulated by interleukin-4 (IL-4) and interleukin-13 (IL-13) in eosinophilic, Type 2 helper T cell (Th2)-mediated airway inflammation.
  • $\text{FeNO} \ge 40\text{ ppb}$ in adults ($\ge 35\text{ ppb}$ in children) is positive, highly suggestive of eosinophilic inflammation and responsiveness to inhaled corticosteroids (ICS).
  • Values between $25\text{–}39\text{ ppb}$ represent an intermediate gray zone; $< 25\text{ ppb}$ makes active eosinophilic asthma unlikely.
• Spirometry & Bronchodilator Reversibility (BDR):
  • Obstructive defect: Post-bronchodilator $\text{FEV}_1/\text{FVC} < 0.70$ (or below the lower limit of normal [LLN]).
  • Positive BDR: An improvement in $\text{FEV}_1$ of $\ge 12%$ AND $\ge 200\text{ mL}$ measured 15–20 minutes following $400\ \mu\text{g}$ inhaled salbutamol via a spacer.
• Peak Expiratory Flow (PEF) Variability:
  • Monitored twice daily (morning and evening) over a minimum of 2 to 4 weeks.
  • Diurnal variability $> 20%$ calculated as: $[(\text{Highest PEF} - \text{Lowest PEF}) / \text{Mean PEF}] \times 100$.
• Direct Bronchial Provocation Challenge:
  • Performed in specialized lung function laboratories when spirometry and FeNO are equivocal.
  • Inhaled methacholine or histamine: A provocative concentration causing a $20%$ fall in $\text{FEV}1$ ($\text{PC}{20}$) of $\le 8\text{ mg/mL}$ confirms bronchial hyperresponsiveness.

---

2. Chronic Asthma: Stepwise Pharmacological Management Ladder

Contemporary management prioritizes anti-inflammatory therapy at every step, minimizing reliance on short-acting $\beta_2$-agonist (SABA) monotherapy to reduce the risk of severe exacerbations and asthma-related mortality.

Maintenance and Reliever Therapy (MART) vs. Traditional Stepwise Regimens

• MART Strategy: Utilizes a single inhaler containing an inhaled corticosteroid (ICS; budesonide or beclometasone) combined with the rapid-onset, long-acting $\beta_2$-agonist formoterol. Because formoterol has a rapid onset of action (1–3 minutes) identical to salbutamol, patients take regular daily maintenance doses and use the same inhaler for as-needed symptom relief, automatically titrating their anti-inflammatory ICS dose during early flare-ups.
• Legacy stepwise ladder (pre-2024 BTS/SIGN, still quoted by older question banks - know it, but know it has been superseded for chronic management by the 2024 joint guideline):
  1. Step 1: As-needed SABA alone for patients with very infrequent, short-lived symptoms and normal baseline lung function (or low-dose ICS taken concurrently whenever SABA is inhaled).
  2. Step 2: Regular low-dose ICS (e.g., beclometasone dipropionate $200\text{–}400\ \mu\text{g/day}$ or budesonide $200\text{–}400\ \mu\text{g/day}$) plus SABA as needed.
  3. Step 3 (Add-on Therapy): Add a Long-Acting $\beta_2$-Agonist (LABA; formoterol or salmeterol) in a fixed-dose combination with low-dose ICS, or initiate a low-dose ICS/formoterol MART regimen.
  4. Step 4: Increase ICS to medium dose ($400\text{–}800\ \mu\text{g/day}$ beclometasone equivalent), or add a Leukotriene Receptor Antagonist (LTRA) (montelukast $10\text{ mg}$ oral daily; particularly effective in aspirin-exacerbated respiratory disease [AERD / Samter's triad: asthma, nasal polyps, aspirin sensitivity] and exercise-induced bronchoconstriction) or a Long-Acting Muscarinic Antagonist (LAMA) (tiotropium Respimat soft mist $5\ \mu\text{g}$ daily).
  5. Step 5 (Severe Refractory Asthma): High-dose ICS ($> 800\ \mu\text{g/day}$), trial of oral theophylline (phosphodiesterase inhibitor; narrow therapeutic window, target serum level $10\text{–}20\text{ mg/L}$), maintenance oral prednisolone (lowest effective dose), and formal referral to a dedicated severe asthma centre for biological phenotyping.

Targeted Biologic Therapies for Severe Refractory Asthma

• Anti-IgE (Omalizumab): Subcutaneous humanized monoclonal antibody targeting free circulating IgE. Indicated in severe persistent allergic asthma with documented positive skin-prick test or specific IgE to perennial aeroallergens, total serum $\text{IgE } 30\text{–}1500\text{ IU/mL}$, and frequent exacerbations.
• Anti-IL-5 Pathways: IL-5 is the cardinal cytokine governing eosinophil differentiation, activation, and survival. Indicated for severe refractory eosinophilic asthma (peripheral blood eosinophils $\ge 300\text{ cells/}\mu\text{L}$):
  • Mepolizumab & Reslizumab: Neutralize circulating IL-5 ligand.
  • Benralizumab: Directed against the IL-5 receptor $\alpha$-subunit (IL-5R$\alpha$), triggering antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer cells, producing near-complete eosinophil depletion.
• Anti-IL-4R$\alpha$ (Dupilumab): Monoclonal antibody targeting the $\alpha$-subunit of the IL-4 receptor, simultaneously blocking IL-4 and IL-13 signaling. Reduces exacerbations and improves $\text{FEV}_1$ in severe eosinophilic or FeNO-driven asthma.
• Anti-TSLP (Tezepelumab): Targets thymic stromal lymphopoietin (TSLP), an epithelial alarmin acting upstream of the inflammatory cascade; effective across both eosinophilic and non-eosinophilic severe asthma phenotypes.

---

3. Acute Severe vs. Life-Threatening Asthma: Recognition & Resuscitation

Correct clinical stratification dictates the urgency of intervention and immediate level of care.

Emergency Management Protocol (BTS/SIGN acute asthma guidance, outside the scope of NG245)

1. Oxygen: High-flow oxygen via reservoir mask to achieve target $\text{SpO}_2\ 94\text{–}98%$. (Unlike COPD, hypoxic drive suppression is not a concern; severe hypoxaemia precipitates fatal ventricular arrhythmias).
2. Nebulised $\beta_2$-Agonists: Salbutamol $5\text{ mg}$ driven by oxygen ($6\text{–}8\text{ L/min}$), repeated every 15–30 minutes or administered via continuous nebulisation ($10\text{ mg/hr}$).
3. Nebulised Anticholinergic: Ipratropium bromide $500\ \mu\text{g}$ added to salbutamol nebulisers every 4–6 hours (or every 20 minutes in acute severe/life-threatening attacks).
4. Systemic Corticosteroids: Oral prednisolone $40\text{–}50\text{ mg}$ daily for at least 5 days (or IV hydrocortisone $100\text{ mg}$ 6-hourly if the patient is vomiting, exhausted, or unable to swallow).
5. Intravenous Magnesium Sulphate: $1.2\text{–}2.0\text{ g}$ IV infusion over 20 minutes for patients with acute severe asthma not responding to initial nebulisers or those presenting with life-threatening features. Acts by blocking smooth muscle calcium influx, promoting rapid bronchial relaxation.
6. Intravenous Aminophylline: Consider in ICU/HDU settings if unresponsive to inhaled bronchodilators and IV magnesium ($5\text{ mg/kg}$ loading dose over 20 minutes if not on maintenance theophylline, followed by $0.5\text{–}0.7\text{ mg/kg/hr}$ infusion). Requires therapeutic drug monitoring.
7. Intubation & Invasive Mechanical Ventilation: Mandatory indications include respiratory arrest, profound hypercapnic coma, deteriorating exhaustion, or refractory severe hypoxia despite maximal medical therapy.

---