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Challenging the paradigm: moving from umbrella labels to treatable traits in airway disease

Andrew Bush, Ian D. Pavord
Breathe 2021 17: 210053; DOI: 10.1183/20734735.0053-2021
Andrew Bush
1Paediatrics and Paediatric Respirology, Imperial Centre for Paediatrics and Child Health, Imperial College London, London, UK
2Royal Brompton and Harefield NHS Foundation Trust, London, UK
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  • For correspondence: a.bush@imperial.ac.uk
Ian D. Pavord
3Respiratory Medicine, Respiratory Medicine Unit and Oxford Respiratory NIHR BRC, Nuffield Dept of Medicine, University of Oxford, Oxford, UK
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Tables

  • Table 1

    The different molecular sub-phenotypes of cystic fibrosis

    Mutation classDefectExemplar mutationsCorrective therapy
    IPremature stop codon leading to a truncated transcript which is destroyedG542X, W1282XNone available, compounds which override premature termination codons being explored
    Candidate for gene therapy
    IIAbnormal protein is synthesised but destroyed, not trafficked to cell membraneDF508Corrector–potentiator combinations, e.g. Trikafta
    IIIImpaired anion conductance functionG551DThe potentiator ivacaftor
    IVDecreased channel opening timeR117HThe potentiator ivacaftor
    VLess CFTR protein reaches the cell surface3849+10 kb C>TSplicing correctors when available, possibly ivacaftor
    VIProtein is abnormally unstable at the cell surfacec.120del23Promote stability when medications available
    VIINo mRNA produced1717-1G->ANo therapies available
    Candidate for gene therapy

    Note that mutations may fall into more than one subcategory. For example, DF508, a class II mutation, is also unstable at the cell surface (class VI).

    • Table 2

      Different phenotypes of paediatric and adult airway disease

      DiagnosisAirway inflammationInfectionFixed airflow obstructionVariable airflow obstructionOther featuresTreatments
      Year one wheeze [97]NoNot known, may be acute viralMay be presentMay be present, likely bronchospasm, could be malacia, mucus or airway malaciaMay occur recurrently
      Seems likely unrelated to later wheeze, poorly understood
      Not ICS
      Can trial SABA or ipratropium
      Preschool wheezeMostly none, but may be eosinophilicAcute viral, bacterial or bothOften presentYes, likely bronchospasm but may be a component of malaciaMay occur recurrentlyICS only if evidence of airway eosinophilia
      Can trial SABA or ipratropium
      School-age asthmaUsually eosinophilic, but may be pauci-granulocyticAcute viral, bacterial or bothOften present related to impaired airway developmentYesCommonly associated with sensitisation to aeroallergens
      Rhinitis, eczema and food allergy often coexist
      ICS if eosinophilic, SABA, LABA, LTRA
      ?LAMA, AZM for pauci-granulocytic
      Aspiration syndromesNeutrophilicMay be bacterial, especially anaerobesOften acquiredMay have bronchospasm
      May have variable atelectasis
      Neuromuscular disease; structural anatomical abnormalitiesTreat underlying cause
      ObesityMay be eosinophilic [87], or IL-6 mediated [88] (systemic inflammation)Not knownDysanaptic airway growth  [89]May have bronchospasm
      May have variable atelectasis
      Obstructive sleep apnoea
      Metabolic syndrome
      Weight reduction
      Ensure there really is an airway disease, not deconditioning
      ICS only if evidence of airway eosinophilia; can trial SABA or ipratropium
      Persistent bacterial bronchitisNeutrophilicBacterial, viralNot well studied, probably not early onYes, intraluminal secretionsMay occur recurrently
      Coarse crackles, squeaks and intraluminal mucus often seen in adults (diffuse panbronchiolitis type pattern)
      Oral co-amoxiclav for 2 weeks [90]; investigate if no response or relapses
      Long-term macrolides often highly effective but must exclude an underlying diagnosis [91]
      CF, PCD, bronchiectasisNeutrophilicBacterial, viralYes, often progressiveYes, intraluminal secretionsMay occur recurrently
      Coarse crackles, squeaks and intraluminal mucus often seen
      Antibiotics, airway clearance, see standard guidelines [96]
      (Chronic) obliterative bronchiolitisNone in chronic phaseNone in chronic phaseYesNoAssociated with autoimmunity in adults (i.e. rheumatoid arthritis)
      Florid form seen in graft versus host disease
      None
      Chronic bronchiolitis (chILD)LymphocyticNoneNot well studied, probably not early onNot well studied, probably notInvestigate and treat underlying cause, usually an immunodeficiency
      Lung disease of prematurityNone unless also atopic [92]NoneYes, even in late preterm and early term survivors [93]Yes, bronchodilator reversible [94]Frequent comorbidities include neurodevelopmental handicap, retinopathy of prematurity, abnormal control of respirationBronchodilators as needed, not ICS unless coincidentally atopic
      Sickle cell anaemia [98]NoneNoneYesNoPainful and occlusive vascular crises in multiple organsSee standard guidelines, no airway disease treatment unless coincidentally atopic
      Post NEHI [95]Probably noneNoneProbably, not well studiedProbably, not well studiedNot well studied; not ICS responsive, SABA as needed
      Tracheo-bronchomalacia [99]NoneNone unless associated with aspirationNone unless associated with a relevant comorbidityYes, may be worsened by SABATreat underlying cause along standard guidelines and any secondary infection with antibiotics and airway clearance
      Adult-onset asthma (most likely adult recrudescence rather than arising de novo)Highly eosinophilicUnusualCan occurShort-term variable airflow obstruction often not prominent, although airflow obstruction is seen in the context of an attackRecurrent asthma attacks often the most prominent manifestation
      Mucus plugging may be a key mechanism for non-bronchodilator airflow obstruction
      Chronic rhinosinusitis and nasal polyposis commonly seen
      ICS
      Type-2 biologics often highly effective
      COPDVariable (all of the above can be seen)Viral and bacterialBy definitionCan be presentHighly heterogeneous condition, likely related to all of the above; multiple systemic comorbidities associatedBronchodilators are the mainstay
      Corticosteroids helpful if evidence of type-2 inflammation
      Unexplained chronic coughMay be lymphocytic but not well studiedUnusualNoNoCommon in perimenopausal women
      Heightened cough reflex
      No well-established treatments, although P2×3 antagonists look promising

      AZM: azithromycin; chILD: children's interstitial lung disease; ICS: inhaled corticosteroids; IL: interleukin; LABA: long-acting β2-agonist; LAMA: long-acting muscarinic agents; LTRA: leukotriene receptor antagonist; NEHI: neuroendocrine cell hyperplasia of infancy; SABA: short-acting β2-agonist.

      • Table 3

        Potential biologicals for treatment of severe paediatric asthma

        BiologicalMode of actionLicensing status (UK)Indications
        OmalizumabBinds IgE preventing binding to the high-affinity IgE receptor (FceRI) on mast cells and basophils
        May also have antiviral effects
        Age 6 years and overIgE between 30 and 1300 IU·mL−1
        (In the UK) ≥4 prednisolone bursts per year, aeroallergen sensitised, adherent to standard therapy
        Dose depends on weight and IgE levels
        MepolizumabBinds circulating IL-5Age 6 years and overBlood eosinophils ≥150 cells per μL
        (In the UK) ≥4 prednisolone bursts per year, aeroallergen sensitised, adherent to standard therapy
        ReslizumabBinds circulating IL-5Not licensedNot applicable
        BenralizumabBinds IL-5 receptorNot licensedNot applicable
        DupilumabBinds IL-4/IL-13 receptorAge 12 years and overOnly licensed for atopic eczema
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      Challenging the paradigm: moving from umbrella labels to treatable traits in airway disease
      Andrew Bush, Ian D. Pavord
      Breathe Sep 2021, 17 (3) 210053; DOI: 10.1183/20734735.0053-2021

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      Challenging the paradigm: moving from umbrella labels to treatable traits in airway disease
      Andrew Bush, Ian D. Pavord
      Breathe Sep 2021, 17 (3) 210053; DOI: 10.1183/20734735.0053-2021
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      • Article
        • Abstract
        • Abstract
        • Introduction
        • The “wet and crackly” umbrella: how have we progressed?
        • The “dry, wheezy umbrella”: where are we now?
        • The future: where from here?
        • Footnotes
        • References
      • Figures & Data
      • Info & Metrics
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      • Paediatric pulmonology
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      • Management of difficult-to-treat asthma in adolescence and young adults
      • Respiratory complications of obesity
      • Diagnosis and management of PH in infants with BPD
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