Tables
- Table 1
The different molecular sub-phenotypes of cystic fibrosis
Mutation class Defect Exemplar mutations Corrective therapy I Premature stop codon leading to a truncated transcript which is destroyed G542X, W1282X None available, compounds which override premature termination codons being explored
Candidate for gene therapyII Abnormal protein is synthesised but destroyed, not trafficked to cell membrane DF508 Corrector–potentiator combinations, e.g. Trikafta III Impaired anion conductance function G551D The potentiator ivacaftor IV Decreased channel opening time R117H The potentiator ivacaftor V Less CFTR protein reaches the cell surface 3849+10 kb C>T Splicing correctors when available, possibly ivacaftor VI Protein is abnormally unstable at the cell surface c.120del23 Promote stability when medications available VII No mRNA produced 1717-1G->A No therapies available
Candidate for gene therapyNote 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
Diagnosis Airway inflammation Infection Fixed airflow obstruction Variable airflow obstruction Other features Treatments Year one wheeze [97] No Not known, may be acute viral May be present May be present, likely bronchospasm, could be malacia, mucus or airway malacia May occur recurrently
Seems likely unrelated to later wheeze, poorly understoodNot ICS
Can trial SABA or ipratropiumPreschool wheeze Mostly none, but may be eosinophilic Acute viral, bacterial or both Often present Yes, likely bronchospasm but may be a component of malacia May occur recurrently ICS only if evidence of airway eosinophilia
Can trial SABA or ipratropiumSchool-age asthma Usually eosinophilic, but may be pauci-granulocytic Acute viral, bacterial or both Often present related to impaired airway development Yes Commonly associated with sensitisation to aeroallergens
Rhinitis, eczema and food allergy often coexistICS if eosinophilic, SABA, LABA, LTRA
?LAMA, AZM for pauci-granulocyticAspiration syndromes Neutrophilic May be bacterial, especially anaerobes Often acquired May have bronchospasm
May have variable atelectasisNeuromuscular disease; structural anatomical abnormalities Treat underlying cause Obesity May be eosinophilic [87], or IL-6 mediated [88] (systemic inflammation) Not known Dysanaptic airway growth [89] May have bronchospasm
May have variable atelectasisObstructive sleep apnoea
Metabolic syndromeWeight reduction
Ensure there really is an airway disease, not deconditioning
ICS only if evidence of airway eosinophilia; can trial SABA or ipratropiumPersistent bacterial bronchitis Neutrophilic Bacterial, viral Not well studied, probably not early on Yes, intraluminal secretions May 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, bronchiectasis Neutrophilic Bacterial, viral Yes, often progressive Yes, intraluminal secretions May occur recurrently
Coarse crackles, squeaks and intraluminal mucus often seenAntibiotics, airway clearance, see standard guidelines [96] (Chronic) obliterative bronchiolitis None in chronic phase None in chronic phase Yes No Associated with autoimmunity in adults (i.e. rheumatoid arthritis)
Florid form seen in graft versus host diseaseNone Chronic bronchiolitis (chILD) Lymphocytic None Not well studied, probably not early on Not well studied, probably not Investigate and treat underlying cause, usually an immunodeficiency Lung disease of prematurity None unless also atopic [92] None Yes, even in late preterm and early term survivors [93] Yes, bronchodilator reversible [94] Frequent comorbidities include neurodevelopmental handicap, retinopathy of prematurity, abnormal control of respiration Bronchodilators as needed, not ICS unless coincidentally atopic Sickle cell anaemia [98] None None Yes No Painful and occlusive vascular crises in multiple organs See standard guidelines, no airway disease treatment unless coincidentally atopic Post NEHI [95] Probably none None Probably, not well studied Probably, not well studied Not well studied; not ICS responsive, SABA as needed Tracheo-bronchomalacia [99] None None unless associated with aspiration None unless associated with a relevant comorbidity Yes, may be worsened by SABA Treat 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 eosinophilic Unusual Can occur Short-term variable airflow obstruction often not prominent, although airflow obstruction is seen in the context of an attack Recurrent 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 seenICS
Type-2 biologics often highly effectiveCOPD Variable (all of the above can be seen) Viral and bacterial By definition Can be present Highly heterogeneous condition, likely related to all of the above; multiple systemic comorbidities associated Bronchodilators are the mainstay
Corticosteroids helpful if evidence of type-2 inflammationUnexplained chronic cough May be lymphocytic but not well studied Unusual No No Common in perimenopausal women
Heightened cough reflexNo 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
Biological Mode of action Licensing status (UK) Indications Omalizumab Binds IgE preventing binding to the high-affinity IgE receptor (FceRI) on mast cells and basophils
May also have antiviral effectsAge 6 years and over IgE 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 levelsMepolizumab Binds circulating IL-5 Age 6 years and over Blood eosinophils ≥150 cells per μL
(In the UK) ≥4 prednisolone bursts per year, aeroallergen sensitised, adherent to standard therapyReslizumab Binds circulating IL-5 Not licensed Not applicable Benralizumab Binds IL-5 receptor Not licensed Not applicable Dupilumab Binds IL-4/IL-13 receptor Age 12 years and over Only licensed for atopic eczema
Vol 17 Issue 3
Table of Contents
Challenging the paradigm: moving from umbrella labels to treatable traits in airway disease
