TABLE 1.

Summary of significant comorbidities in difficult asthma

Comorbidity	Impact on asthma	Diagnosis	Treatment	Treatment impact on asthma outcomes
COPD	Confounder of PROMs of asthma control, especially dyspnoea scores, cough and wheeze	Appropriate clinical context plus spirometry evidence of fixed airflow obstruction ±CT-evident emphysema	As with asthma, LABA±LAMA±ICS Azithromycin prophylaxis ±Pulmonary rehabilitation ±LTOT/home NIV ±Lung volume reduction techniques	ICS±LABA for ACO improves lung function LAMA and pulmonary rehabilitation may improve dyspnoea Anti-IL-4/IL-13 and anti-IL-5 receptor drugs may improve lung physiology and exacerbation frequency, respectively
Allergic rhinitis	May contribute to or worsen cough via post-nasal drip Direct effects on lower airway changes are unclear	Clinical history (rhinorrhoea, sneezing, nasal obstruction, pruritus, conjunctivitis) Demonstration of allergen via skin prick/in vitro testing	Trigger avoidance Nasal/oral antihistamines Nasal ICS LTRA Allergen-specific SCIT and SLIT	Nasal ICS treatment may improve asthma control LTRA use improves nasal and asthma control Antihistamines can improve asthma symptoms and bronchial hyperresponsiveness
CRS with or without nasal polyposis	May contribute to or worsen cough via post-nasal drip Nasal polyposis raises possibility of AERD/NERD	3 months of symptoms plus objective proof of mucosal inflammation (CT or nasal endoscopy) ±Visualisation of polyps	Nasal irrigation Nasal ICS FESS, polypectomy or posterior nasal neurectomy in selected patients	Improvement in quality of life and decrease in steroid and antibiotic dependency
ABPA	Worsens pulmonary function, cough, wheeze, mucus production, exacerbation frequency and steroid requirements	Various criteria exist; typically: 1) proven CF or asthma and 2) total IgE >1000 IU·mL−1 and 3) increased Aspergillus sensitisation (IgE) and 4) increased Aspergillus IgG/radiographic changes/peripheral blood eosinophilia	Glucocorticoids and/or azoles Defined best regimen lacks consensus Omalizumab Anti-IL-5/5R and IL-4α receptor antagonist	Glucocorticoids and azoles decrease ABPA exacerbations and improve symptoms Biologics have been helpful in decreasing steroid dosing and decreasing exacerbation frequency
Bronchiectasis	Confounds symptoms of cough and wheeze Associated with frequent exacerbations, decline in lung function and poor quality of life	CT imaging evidence of bronchiectatic airways While not diagnostic, sputum or bronchoscopy derived microbiology samples help guide treatment	Airway clearance education Vaccination Targeted antibiotic therapy based on sputum culture and sensitivity Azithromycin prophylaxis	Unclear: bronchiectasis management can be expected to reduce exacerbation frequency, but specific asthma outcomes have not been assessed
GORD	Responsible for poor control of asthma directly and indirectly Associated with obesity and OSAS	History suggestive of symptomatic reflux Oesophageal pH manometry Endoscopy may demonstrate oesophagitis/laryngopharyngeal inflammation suggestive of GORD	Empiric trial of PPI for 8 weeks Lifestyle modification (head of bed elevation, trigger avoidance, meal timing) Endoscopy in PPI non-responders Surgical management	No asthma benefit for asymptomatic GORD treatment Treatment of symptomatic GORD in asthma patients reduces steroid and reliever use and may improve lung function
Obesity	Associated with high symptom burden, increased frequency of exacerbation and poor quality of life, and steroid resistance	Objective verification of BMI >30 kg·m−2	Weight management strategies and bariatric surgery aiming for >5% body weight loss	>5% body weight loss has been shown to improve spirometry, peak flow and asthma control in adults and children Bariatric surgery has been associated with decreased dependency on asthma medication and reduced hospitalisation
OSAS	Independent risk factor for poor control of asthma	Gold standard is polysomnography, but limited sleep studies, overnight spirometry and validated questionnaire can be used as screening tools	Weight loss Optimisation of nasal/tonsillar disease Mandibular advancement devices CPAP Surgery	CPAP use has shown benefit in asthma symptom control and improvement in lung function in some studies
T2DM	Insulin resistance and metabolic syndrome have been associated with both asthma development and increased exacerbation risk	Any two of: 1) 8-h fasting plasma glucose ≥7.0 mmol·L−1, 2) 2-h plasma glucose ≥11.1 mmol·L−1 during OGTT#, 3) HbA1c ≥6.5% (48 mmol·mol−1), 4) random plasma glucose ≥11.1 mmol·L−1 in a patient with classic symptoms of hyperglycaemia or hyperglycaemic crisis	Lifestyle and dietary optimisation Weight management Anti-hyperglycaemic therapy Comprehensive management of comorbidities such as hypertension and dyslipidaemia	Metformin use in patients with concurrent T2DM and asthma has been associated with reduced asthma exacerbation rates and asthma-related hospitalisation GLP-1RA use is associated with lower asthma exacerbation rates in patients with T2DM and asthma compared with SGLT-2 inhibitors, DPP-4 inhibitors, basal insulin and sulfonylureas
ILO	Mimics poorly controlled asthma Non-response to ICS can result in reflex escalation of asthma therapies with high side-effect burden, including excessive corticosteroids and occasionally intubation	Gold standard is direct laryngoscopy visualising excessive adduction of vocal cord or laryngeal structures ±provocation challenge Flattened inspiratory flow–volume loop at spirometry can suggest ILO Continuous laryngoscopy with exercise is gold standard for EILO	Identifying and modifying environmental and occupational irritants, alongside speech and language therapy for throat relaxation and cough suppression Case series reports of low-dose amitriptyline, botulin toxin and surgical resection	Speech and language therapy retraining interventions have been demonstrated to reduce symptom burden in those with chronic cough refractory to medical management; while such an intervention may therefore reduce corticosteroid use in patients with ILO and asthma, further trials are needed to guide management in ILO
Dysfunctional breathing	Results in disproportionate symptoms of breathlessness, confounding PROMs of asthma	Specialist physiotherapist assessment is required for diagnosis Nijmegen Questionnaire score ≥24 may support a diagnosis	Physiotherapy-led breathing retraining, can be in-person or online	Significant improvements in mean Asthma Control Test and Asthma Quality of Life Questionnaire scores
Anxiety/depression	Reduce treatment adherence, worsen asthma control Panic disorders confounding PROMs of asthma control, namely dyspnoea	World Health Organization International Classification of Diseases 11th Revision criteria	Assessment of symptom severity Risk assessment Education and psychosocial interventions Pharmacotherapy and short interval reassessment Specialist psychiatric assessment as deemed appropriate	Mixed evidence regarding the role of cognitive behavioural and relaxation therapies in improving asthma-related outcomes among those with anxiety or depression No evidence for asthma-specific management strategies

ABPA: allergic bronchopulmonary aspergillosis; ACO: asthma with COPD overlap; AERD/NERD: aspirin/nonsteroidal anti-inflammatory drug-exacerbated respiratory disease; BMI: body mass index; CF: cystic fibrosis; CPAP: continuous positive airway pressure; CRS: chronic rhinosinusitis; CT: computed tomography; DPP-4: dipeptidyl peptidase-4; EILO: exercise-induced laryngeal obstruction; FESS: functional endoscopic sinus surgery; GLP-1RA: glucagon-like peptide-1 receptor agonist; GORD: gastro-oesophageal reflux disease; HbA1c: haemoglobin A1c; ICS: inhaled corticosteroid; IL: interleukin; ILO: inducible laryngeal obstruction; LABA: long-acting β-agonist; LAMA: long-acting muscarinic antagonist; LTOT: long-term oxygen therapy; LTRA: leukotriene receptor antagonist; NIV: noninvasive ventilation; OGTT: oral glucose tolerance test; OSAS: obstructive sleep apnoea syndrome; PPI: proton pump inhibitor; PROMs: patient-reported outcome measures; SCIT: subcutaneous immunotherapy; SGLT-2: sodium/glucose cotransporter-2; SLIT: sublingual immunotherapy; T2DM: type 2 diabetes mellitus. ^#: glucose load equivalent to 75 g anhydrous glucose dissolved in water, with baseline, 1-h and 2-h plasma blood glucose measurement.