Recent Insights into the Management of Inflammation in Asthma

Figures & data

Figure 1 Advantages and disadvantages of commonly used asthma biomarkers.

Abbreviation: FeNO, fractional exhaled nitric oxide.

Table 1 Treatable Traits in Asthma; Evaluation and Management Options

	Trait	Diagnostic Evaluation	Management Options
Pulmonary	Airflow Limitation	Spirometry with FEV1/FVC <0.7	Inhaled corticosteroids, long acting β2 agonists, long-acting antimuscarinic agents.
	Small Airways Disease	Impaired FEF25–75, impaired oscillometry, evidence of air-trapping on plethysmography ± HRCT.	Ultrafine particle inhaled corticosteroids.
	Airway Inflammatory Phenotype (Eosinophilic, Mixed)	Sputum eosinophils (%), blood eosinophil count, FeNO	Inhaled corticosteroids, leukotriene antagonists, oral corticosteroids, monoclonal antibody therapies.
	Airway Inflammatory Phenotype (Neutrophilic)	Sputum neutrophils (%)	?Long-acting antimuscarinic agents, ?prophylactic antibiotics, ?bronchial thermoplasty.
	Airway Inflammatory Phenotype (Paucigranulocytic)	Sputum eosinophils and neutrophils (%)	?Long-acting antimuscarinic agents, ?prophylactic antibiotics, ?bronchial thermoplasty.
	Allergic Fungal Airway Disease	Total IgE, specific IgE to Aspergillus, Aspergillus Precipitins, HRCT chest.	Inhaled/ oral corticosteroids, antifungal agents, monoclonal antibody therapies.
	Aspirin Exacerbated Respiratory Disease	Clinical history & examination, aspirin challenge	Aspirin desensitisation, salicylate lowering diet, inhaled corticosteroids, leukotriene antagonists, oral corticosteroids, monoclonal antibody therapies.
	Airway Infections ± Colonisation	Clinical history, antibiotic history, sputum culture.	Acute/ prophylactic antibiotics.
	Bronchiectasis	Clinical history & examination, HRCT, sputum culture.	Chest clearance, prophylactic antibiotics, nebulised antibiotics.
	Dual COPD	Clinical history & examination, spirometry, transfer factors, HRCT, sputum culture.	Smoking cessation, chest clearance, pulmonary rehabilitation, long acting β2 agonists, long-acting antimuscarinic agents.
Extra-Pulmonary	Rhinitis	Clinical history & examination,	Topical nasal steroids, antihistamines, leukotriene antagonists, nasal rinses, allergen immunotherapy.
	Chronic Rhinosinusitis (± Nasal Polyps)	Clinical history & examination, nasendoscopy, CT sinuses.	Topical nasal steroids, antibiotics, nasal rinses, surgery.
	Gastro-Oesophageal Reflux Disease	Clinical history & examination, upper GI endoscopy, pH monitoring.	Proton pump inhibitors, H2 antagonists, weight loss, surgery.
	Obesity	Body Mass Index	Diet, exercise, medication, bariatric surgery.
	Deconditioning	Clinical history, 6 Minute Walk Test	Exercise.
	Obstructive Sleep Apnoea	Clinical history & examination, Epworth Sleepiness Score, sleep study.	Weight loss, mandibular advancement devices, Continuous Positive Airways Pressure therapy.
	Dysfunctional Breathing	Clinical history & examination, Nijmegen score.	Physiotherapy support.
	Intermittent Laryngeal Dysfunction	Clinical history & examination, indirect laryngoscopy.	Speech therapy support.
	Depression	Clinical history & examination, HADS score.	Psychologist support.
	Anxiety	Clinical history & examination, HADS score.	Psychologist support.
Behavioural	Smoking	Clinical history, exhaled carbon monoxide, urinary cotinine.	Smoking cessation support, nicotine replacement therapy.
	Adherence	Clinical history, prescription pick up data, “smart inhalers”, prednisolone assay.	Patient education, motivational interviewing, self-management guidance.
	Poor Inhaler Technique	Direct assessment.	Patient education.
	Distorted Symptom Perception	Comparison of objective and subjective measures.	Patient education, treatment of relevant psychophysiologic traits.

Abbreviations: FEV₁/FVC, forced expiratory volume in 1 second/ forced vital capacity ratio; FEF_25–75, mid-expiratory flow; HRCT, High-Resolution CT; FeNO, fractional exhaled nitric oxide; COPD, Chronic Obstructive Pulmonary Disease; CT Sinus, Computed Tomography Sinus; GI, Gastrointestinal; HADS, Hospital Anxiety and Depression Score.

Table 2 Comparison of Adult Asthma Chronic Management Guidelines

	Global Initiative for Asthma 2021	National Asthma Education and Prevention Program Guidelines 2021	British Thoracic Society Guidelines 2019
	Non Applicable	Intermittent Asthma: PRN SABA	Suspected Asthma: Can Consider Monitored Initiation of Low Dose ICS
“Step” 1	As-needed low dose ICS/formoterol OR ICS used at the same time as SABA	Regular low dose ICS + PRN SABA OR ICS used at the same time as SABA	Regular low dose ICS + PRN SABA
“Step” 2	As needed low dose ICS/formoterol OR Regular low dose ICS + PRN SABA	Regular and as required low dose ICS/formoterol	Regular low ICS/LABA + PRN SABA OR Low dose maintenance and reliever ICS/LABA
“Step” 3	Low dose maintenance and reliever ICS/formoterol OR Low dose maintenance ICS/LABA + PRN SABA	Regular and as required medium dose ICS/formoterol	Medium dose ICS/LABA +PRN SABA OR Low dose ICS/LABA + LTRA +PRN SABA
“Step” 4	Medium dose maintenance ICS/formoterol + as needed low dose ICS-formoterol OR Medium/high dose maintenance ICS/LABA + PRN SABA	Daily medium-high dose ICS/LABA + LTRA or LAMA + PRN SABA Consider adding asthma biologic	Refer patient to specialist care for consideration of specialist therapies (including asthma biologics)
‘Step’5	Add LAMA Consider high dose ICS/formoterol OR Add on LAMA, consider high dose ICS/LABA Refer for consideration of asthma biologic	Daily high-dose ICS/LABA + PRN SABA + OCS Consider adding asthma biologic

Abbreviations: ICS, inhaled corticosteroids; SABA, short-acting beta-agonist; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; PRN, As needed.

Table 3 Current Biological Treatments in Severe Asthma. Targets, Eligibility, Dosing Regimen and Real World Impact

Biologic Name	Molecular Target	Eligibility Criteria for Adults (Based on EMA)^Citation1^–^Citation5	Dosing Regimen	Real World Impacts
Omalizumab	Free IgE	As add-on therapy to improve asthma control in patients with severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and who have reduced lung function (FEV1 <80%) as well as frequent daytime symptoms or night-time awakenings and who have had multiple documented severe asthma exacerbations despite daily high-dose inhaled corticosteroids, plus a long-acting inhaled beta2-agonist.	2–4 weekly, subcutaneously based on Total IgE level and body weight	Improvement in FEV1, Asthma control, exacerbations, OCS requirements, healthcare utilisation^Citation26,^Citation211,^Citation221
Mepolizumab	IL-5	Severe refractory eosinophilic asthma	100mg, 4 weekly, subcutaneously	Improvement in asthma control, exacerbations, OCS requirements, healthcare utilisation, AQLQ, FEV1^Citation26,^Citation117,^Citation239,^Citation241,^Citation275
Reslizumab	IL-5	Severe eosinophilic asthma inadequately controlled despite high dose inhaled corticosteroids plus another medicinal product for maintenance treatment.	3mg/kg 4 weekly, intravenously over 20–50 minutes	Improvement in exacerbations, OCS requirements, FEV1, healthcare utilisation^Citation233,^Citation240
Benralizumab	Alpha subunit of IL-5 receptor	As an add on maintenance treatment in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus long acting β agonists.	30mg 4 weekly for the first three doses, then 8 weekly subcutaneously	Improvement in exacerbations, OCS requirements, healthcare utilisation, FEV1, AQLQ^Citation243^–^Citation245,^Citation258
Dupilumab	Alpha subunit of IL-4 receptor	Add-on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised fraction of exhaled nitric oxide, who are inadequately controlled with high dose ICS plus another medicinal product for maintenance treatment.	If on OCS + moderate-severe atopic eczema/CRSwNP: loading dose of 600mg followed by 300mg 2 weekly 400mg loading dose followed by 200mg 2 weekly, subcutaneously	Improvement in asthma control, exacerbations, FEV1, OCS requirements^Citation264^–^Citation268

Abbreviations: IgE, immunoglobulin E; FEV₁, forced expiratory volume in 1 second; OCS, oral corticosteroid; AQLQ, asthma quality of life questionnaire; ICS, inhaled corticosteroids; IgE, Immunoglobulin E; IL-5, Interleukin-5; IL-4, Interleukin-4.

Figure 2 Biologic drugs in severe asthma and treatable traits potentially amenable to treatment by them.

Abbreviations: CRSwNP, chronic rhinosinusitis with nasal polyps; EGPA, Eosinophilic Granulomatosis with Polyangiitis.

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