01OverviewDefinition, clinical context and the essential points that orientate the chapter.
Uncontrolled asthma is heterogeneous. Some people have an incorrect or incomplete diagnosis; others receive the wrong device, cannot use it, do not obtain it, face ongoing smoke or occupational exposure, or have untreated rhinitis, reflux symptoms, obesity, sleep-disordered breathing or inducible laryngeal obstruction. These are not trivial exclusions: finding and addressing them can prevent systemic corticosteroid toxicity and inappropriate biologic treatment.
Severe asthma is a retrospective clinical conclusion after structured optimisation, not a synonym for one frightening attack. It generally requires high-dose inhaled corticosteroid plus additional controller treatment, or systemic corticosteroid, to prevent loss of control, and remains uncontrolled despite this. Attack history, lung function, symptom burden and treatment toxicity all matter, and an individual may have severe disease even when spirometry is normal between episodes.
Eosinophilic asthma describes a type 2 inflammatory trait that may predict benefit from selected biologics, but eosinophils are also raised in other disorders. Allergic sensitisation, blood eosinophils, FeNO, exacerbation phenotype, corticosteroid dependence and comorbid nasal polyposis are interpreted together. Omalizumab, anti-IL-5 or IL-5-receptor agents, dupilumab and tezepelumab have different NICE criteria. Choice belongs in a severe-asthma multidisciplinary pathway with explicit response endpoints.
Key points
- Difficult asthma remains uncontrolled for any reason; severe asthma is the smaller subset that stays uncontrolled despite confirmed diagnosis, optimised adherence, technique, exposures, comorbidity and high-intensity treatment.
- Before adding specialist drugs, revisit whether symptoms are asthma: inducible laryngeal obstruction, dysfunctional breathing, obesity, cardiac disease, bronchiectasis and anxiety can coexist or mimic poor control.
- Count attacks, urgent care, systemic corticosteroid courses and functional restriction; a symptom score alone can miss serious future risk.
- Pharmacy refill data, direct inhaler observation and a non-judgemental adherence discussion are core investigations, not administrative extras.
- Blood eosinophils and FeNO are treatment-responsive and biologically variable; a low result during systemic corticosteroid exposure does not reliably exclude type 2 disease.
- Biologic eligibility is drug-specific and governed by current NICE technology appraisals, licensed indications and specialist commissioning pathways rather than a single universal eosinophil cut-off.
- Biologics are add-on maintenance therapies, not rescue treatment; inhaled corticosteroid must continue and oral corticosteroid reduction must be supervised.
- Frequent short-acting beta2 agonist use, repeated oral corticosteroid bursts and poor collection of preventer inhalers are high-risk signals requiring active review.
- Look for allergic bronchopulmonary aspergillosis, eosinophilic granulomatosis with polyangiitis and parasitic or haematological causes when eosinophilia or systemic features are disproportionate.
- Refer to a specialist severe-asthma service when diagnosis or phenotype is uncertain, attacks continue despite optimisation, maintenance oral corticosteroid is needed or a biologic may be appropriate.
02AetiologyUnderlying causes, associations and risk factors, with why each one matters.
Persistent type 2 inflammation
Eosinophilic cytokine pathways can remain active despite substantial inhaled treatment, sometimes associated with adult onset, nasal polyps or corticosteroid responsiveness.
Modifiable difficult asthma
Poor adherence, incorrect inhaler technique, smoking, allergen or workplace exposure and untreated comorbidity commonly imitate treatment-resistant disease.
Alternative or overlapping disease
Inducible laryngeal obstruction, bronchiectasis, ABPA, eosinophilic vasculitis and cardiac disease may produce ongoing symptoms attributed incorrectly to asthma.
Non-type 2 mechanisms
Obesity, irritant exposure and other inflammatory patterns can drive severe symptoms without prominent eosinophilia, limiting the value of a single biomarker.
03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.
- 1Persistent airway inflammation
Ongoing eosinophilic or alternative inflammation maintains mucosal oedema, mucus production and bronchial hyperresponsiveness between attacks, thereby altering ventilation, gas transfer or respiratory mechanics.
- 2Recurrent variable obstruction
Trigger-induced smooth-muscle contraction narrows already inflamed airways, producing episodic symptoms, gas trapping and exacerbations, which links the underlying lesion to the observed respiratory dysfunction.
- 3Structural remodelling
Repeated injury thickens basement membrane and airway muscle, creating fixed obstruction and reducing the apparent response to bronchodilation.
- 4Systemic treatment burden
Frequent corticosteroid exposure suppresses inflammation temporarily but generates metabolic and immune harm that becomes part of the disease burden.
04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.
Repeated systemic corticosteroid courses, emergency attendance, admission, previous ventilation, rising reliever use or abrupt loss of control predicts future harm even when the person appears comfortable at a planned review.
Poor collection or technique, an unsuitable device, smoking, occupational exposure, allergen burden, misunderstanding or untreated comorbidity explains ongoing symptoms before severe disease has been established.
Recurrent attacks with blood eosinophilia, raised FeNO, nasal polyposis, atopy or corticosteroid responsiveness suggests type 2 inflammation, but biomarkers must be timed against corticosteroid exposure and alternative causes.
Neuropathy, purpura, renal or cardiac features, constitutional illness, pulmonary infiltrates or marked persistent eosinophilia should trigger urgent assessment for vasculitis, infection, drug reaction, haematological disease or another systemic cause.
Weight gain, hypertension, diabetes, osteoporosis, cataract, infection, mood change, myopathy or adrenal suppression may reflect cumulative oral and high-dose inhaled corticosteroid exposure and require active prevention and monitoring.
05InvestigationsWhat to request, why it matters and how to interpret it.
Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.
- 01
Structured diagnostic reassessment with objective asthma evidenceFirst step - Why
- Confirm variable airway disease before labelling severe asthma.
- Interpretation and limitations
- Review original spirometry, bronchodilator variability, PEF or challenge evidence and treatment timing. Normal current tests on high-dose therapy do not erase prior objective evidence, but unsupported diagnosis should prompt specialist re-evaluation.
- 02
Observed inhaler technique and prescribing record review - Why
- Identify remediable delivery and adherence barriers.
- Interpretation and limitations
- Match actual collection, device activation, inspiratory flow and regimen understanding to the prescription. Approach discrepancies collaboratively; cost, dexterity, cognition, beliefs and adverse effects can each require a different intervention.
- 03
Blood eosinophils, FeNO and total or specific IgE - Why
- Characterise type 2 and allergic traits for specialist treatment.
- Interpretation and limitations
- Use repeated historical values and document systemic or inhaled corticosteroid exposure. These biomarkers support phenotype and eligibility but do not independently diagnose severe asthma or select one biologic.
- 04
Full blood count, renal, liver, glucose and bone-risk assessment - Why
- Find alternative eosinophilia causes and treatment toxicity.
- Interpretation and limitations
- Persistent disproportionate eosinophilia needs a broader differential guided by travel, drugs and systemic signs. Metabolic and skeletal results establish a baseline for corticosteroid harm-reduction planning.
- 05
Chest imaging and full pulmonary physiology - Why
- Identify structural disease and quantify airway impairment.
- Interpretation and limitations
- Use chest radiograph, CT, lung volumes and gas transfer selectively for fixed obstruction, recurrent focal infection, crackles, haemoptysis or discordant breathlessness. Bronchiectasis, emphysema and central airway disease can alter treatment.
- 06
Targeted comorbidity and mimic assessment - Why
- Separate asthma activity from parallel symptom drivers.
- Interpretation and limitations
- Investigate rhinosinusitis, nasal polyps, sleep apnoea, inducible laryngeal obstruction, dysfunctional breathing, obesity, reflux symptoms, cardiac disease and occupational exposure according to history rather than ordering an indiscriminate panel.
06Differential diagnosisRealistic alternatives and the features that help distinguish them.
Poor adherence or technique
Objective prescription history, device observation and biomarker changes under supervised treatment may reveal inadequate medicine delivery rather than biological refractoriness.
Inducible laryngeal obstruction
Abrupt inspiratory symptoms, throat tightness and laryngeal closure during symptomatic laryngoscopy distinguish it from lower-airway bronchoconstriction.
Eosinophilic granulomatosis with polyangiitis
Neuropathy, purpura, renal or cardiac disease and marked systemic eosinophilic features suggest vasculitis rather than isolated eosinophilic asthma.
Allergic bronchopulmonary aspergillosis
Fungal sensitisation, high total IgE, mucus impaction and central bronchiectasis support ABPA as a treatable driver.
Cardiorespiratory comorbidity
Obesity, sleep apnoea, reflux, dysfunctional breathing, COPD or heart failure may dominate breathlessness despite objectively controlled airway inflammation.
07ManagementImmediate care, first-line treatment, alternatives and escalation.
01RebuildConfirm before escalatingFirst stepEscalationSymptoms or attacks persist despite apparently high-intensity asthma treatment.+
- 1Reconstruct the diagnosis from symptom pattern, objective variable airflow evidence, previous attacks and response, considering airway and non-airway mimics.
- 2Observe every inhaler, reconcile prescriptions with collections and daily use, and switch device or education strategy when delivery is unreliable.
- 3Identify smoke, vaping, occupational or allergen exposure and treat relevant rhinitis, obesity, sleep disorder, dysfunctional breathing or laryngeal dysfunction.
- 4Optimise NICE-recommended inhaled treatment and an action plan, then reassess attacks, control and lung function over an appropriate interval before calling disease severe.
02PhenotypeBuild a specialist trait profileAsthma remains uncontrolled after structured optimisation or requires maintenance systemic corticosteroid.+
- 1Refer to a commissioned severe-asthma service and collate attack history, hospital care, systemic steroid exposure, adherence evidence and prior pulmonary function.
- 2Review repeated eosinophils, FeNO, allergic sensitisation, total IgE, nasal polyposis and corticosteroid timing, then investigate disproportionate eosinophilia or radiological abnormalities.
- 3At multidisciplinary review, match the dominant treatable traits and current NICE technology-appraisal criteria to appropriate options, including biologic or non-biologic strategies.
- 4Agree one primary response aim and measurable secondary outcomes before starting specialist therapy, alongside a plan for non-response or adverse effects.
03BiologicStart and evaluate add-on therapyThe specialist team confirms eligibility for a named biologic under current guidance.+
- 1Explain mechanism, realistic aims, injection arrangements, hypersensitivity advice, pregnancy considerations and why existing inhaled treatment continues.
- 2Record baseline attacks, oral corticosteroid burden, symptom score, lung function and relevant phenotype markers before the first dose.
- 3Review at the drug- and pathway-specific assessment point for meaningful improvement, adverse effects and adherence to background treatment; do not infer response from eosinophil suppression alone.
- 4Continue only when agreed benefit and eligibility are met; switch or stop through the specialist pathway rather than overlapping biologics empirically.
04Steroid safetyReduce systemic corticosteroid harmRepeated courses, maintenance prednisolone or suspected adrenal suppression occurs.+
- 1Quantify cumulative and current exposure, document complications and provide prevention appropriate to bone, metabolic, ocular, infection and gastrointestinal risk.
- 2Optimise inhaled and specialist therapy to reduce future courses, but never abruptly withdraw maintenance systemic corticosteroid or high-dose treatment.
- 3Use an endocrinology-informed taper when adrenal suppression is possible, issue steroid emergency information where indicated and provide sick-day advice.
- 4Monitor both asthma deterioration and adrenal symptoms during reduction, with rapid access to the severe-asthma team if control worsens.
Key medicines and prescribing safety4 treatments · regimens, roles and cautions+
High-intensity inhaled corticosteroid-formoterol maintenance and reliever therapy
Use the current NICE step and exact locally selected inhaler strength, maintenance schedule and as-needed limit after specialist technique and adherence review.Only licensed ICS-formoterol products and regimens should be used for MART. High use requires prompt review; monitor local and systemic corticosteroid effects, and do not add a separate LABA-containing inhaler inadvertently.
Mepolizumab for eligible severe eosinophilic asthma
For adults and adolescents, 100 mg subcutaneously once every four weeks as specialist-initiated long-term add-on treatment under current NICE criteria.Not for acute attacks and not a reason to stop inhaled or oral corticosteroid abruptly. Confirm product, age and commissioning eligibility; monitor hypersensitivity, infection context and agreed clinical response, reviewing ongoing need at least annually.
Benralizumab for eligible severe eosinophilic asthma
Use 30 mg subcutaneously every four weeks for the first three doses, then every eight weeks, through a specialist severe-asthma pathway.Eligibility follows the current NICE appraisal and licence, not eosinophil count alone. It does not treat an acute attack; continue background asthma therapy and supervise any oral corticosteroid reduction because adrenal suppression may be present.
Tezepelumab for eligible severe asthma
Use the licensed subcutaneous maintenance regimen at four-week intervals when a specialist confirms the current NICE technology-appraisal criteria are met.Commissioning criteria and comparison with other biologics must be checked at initiation. It is not rescue therapy; observe hypersensitivity advice, continue inhaled corticosteroid and judge benefit by attacks, control and steroid exposure.
08ComplicationsImportant consequences, why they occur and why they matter clinically.
Life-threatening exacerbation
Sudden widespread obstruction can cause severe hypoxaemia, respiratory muscle exhaustion, hypercapnia and arrest, creating an additional need for recognition and targeted treatment.
Fixed airflow limitation
Chronic remodelling may leave persistent obstruction and reduced exercise capacity even when current inflammatory activity is suppressed.
Systemic corticosteroid toxicity
Repeated or maintenance exposure increases osteoporosis, diabetes, obesity, infection, cataract, adrenal suppression and psychological morbidity, creating an additional need for recognition and targeted treatment.
Biological treatment risk
Advanced phenotype-led therapies can cause injection reactions, infection-related concerns or ineffective treatment if the underlying trait was misidentified.
Psychosocial and occupational loss
Unpredictable attacks, medicine burden and avoidance of triggers can disrupt education, work, sleep, exercise and mental health.
09Monitoring and follow-upTreatment response, safety checks and longer-term review.
- Record severe attacks, emergency attendance, admissions, systemic corticosteroid courses and maintenance dose because these outcomes drive risk and biologic response assessment.
- Track a validated control score, night symptoms, reliever use, activity and work impact alongside spirometry or PEF; no single measure captures severe-asthma control.
- Repeat eosinophils and FeNO only with treatment timing documented; biomarker suppression can confirm pharmacological effect but does not by itself prove clinical benefit.
- Monitor weight, blood pressure, glucose, bone health, eyes, infection and adrenal risk in people exposed to repeated or maintenance systemic corticosteroid.
- At each biologic review assess administration, adverse reactions, background inhaler adherence, attacks and corticosteroid burden against the pre-agreed continuation criteria.
10Special situationsVariants, exceptions and circumstances that change the usual approach.
Severity is treatment-dependent
A person controlled only by high-intensity therapy may still have severe asthma. Conversely, uncontrolled symptoms on an uncollected inhaler do not establish biological treatment resistance.
Historical biomarkers matter
Systemic corticosteroid can rapidly lower eosinophils and FeNO. A well-documented pre-treatment value may be more phenotype-informative than a normal result during recent treatment.
Symptoms and attacks diverge
Obesity, dysfunctional breathing or ILO can drive daily breathlessness while eosinophilic inflammation drives attacks. Treating only one domain may leave the other unchanged.
Biologic response is clinical
Fewer attacks, reduced systemic corticosteroid exposure, better control and improved function matter more than a dramatic laboratory biomarker fall without lived benefit.
Eosinophilia has a differential
Marked or persistent eosinophilia with systemic features is not automatically an asthma phenotype. Vasculitis, parasite, drug and haematological causes require directed assessment before immunomodulation.
11Common pitfallsFrequent interpretation and management errors.
- 01
Calling asthma severe before confirming the diagnosis, device technique, actual adherence and relevant exposures.
- 02
Escalating inhalers for breathlessness caused predominantly by laryngeal dysfunction, obesity, cardiac disease or deconditioning.
- 03
Excluding eosinophilic disease from one low blood count obtained after systemic corticosteroid treatment.
- 04
Selecting a biologic from a biomarker alone without checking current NICE eligibility, comorbidity and attack history.
- 05
Stopping inhaled or maintenance oral corticosteroid abruptly when a biologic is started.
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Continuing specialist therapy indefinitely without a documented baseline, response endpoint and non-response decision.