ASTHMA UPDATE

‘We can’t diagnose asthma until <insert arbitrary age>'

'Asthma’ is no more than a clinical description of symptoms such as wheeze, breathlessness and cough, as arthritis describes red, painful joints; neither is a 21st century diagnosis.

The use of low-dose inhaled corticosteroids (ICS) to treat children with asthma can be life-transforming, and this is confirmed repeatedly when they are made widely available for the first time in a low and middle income setting. ¹ However, reading the National Report on Asthma Deaths (NRAD)² among other documents makes it very clear that progress has stalled. In response to this perception, a Lancet commission has recently been published.³ This annotation reviews some of the implications of that document for paediatrics.

The first proposal is that ‘asthma’ is no more than a clinical description of symptoms such as wheeze, breathlessness and cough, as arthritis describes red, painful joints; neither is a 21st century diagnosis. The proper response of a family whose child has been given a diagnosis of asthma is, ‘what sort of asthma does my child have?' So the Commission proposes that as far as possible, the airway disease should be deconstructed into identifiable aspects such as airflow limitation, eosinophilic airway inflammation, airway infection and impaired airway defences, and altered cough reflex sensitivity and efficacy. The emphasis is on defining in particular 'treatable traits’ of airway disease,⁴ which include such extra-pulmonary comorbidities as obesity and allergic rhino-conjunctivitis, and social and environmental factors, in particular adherence. There are important implications of this approach in preschool children, school-age children with an associated airway or systemic disease and also in the era of the new biologicals.

The wheezing preschool child has traditionally been ‘phenotyped’ on the history as having episodic viral wheeze or multiple trigger wheeze,⁵ which is limited in many ways,⁶ and can hardly be said to be worthy of 21st century practice. Some but not all likely have eosinophilic airway inflammation, and thus be responsive to ICS. TheLancetapproach is to urge characterisation of the airway disease; it is perfectly possible with patience and a good technician to determine if there is fixed or variable airflow obstruction using spirometry in preschool children.⁷ Induced sputum can be used even in very young children to determine infection status,^8,9 although induced sputum cytology in the preschool child does not predict airway eosinophilia9 unlike in older children.¹⁰ There is increasing evidence that the peripheral blood eosinophil count predicts airway eosinophilia,⁹ and response to ICS, as does atopic sensitisation,¹¹ neither of which are difficult to determine even in primary care. So rather than 'not diagnosing asthma’, we should be asking 'does this preschool child have eosinophilic airway inflammation and thus is ICS responsive?' We need to get out of the stagnant rut of making treatment decisions based merely on a conversation with a carer who by definition is reporting the child’s state second hand.

Frequently, the question is asked, do children with, for example, cystic fibrosis (CF), bronchopulmonary dysplasia (BPD) and sickle cell disease (SCD) have asthma?12–14 Rather the question should be asked, what sort of airway disease do they have? Do they have variable airflow obstruction that may be responsive to inhaled β-2 agonist, or eosinophilic inflammation responsive to ICS? So BPD survivors have fixed and variable airflow obstruction, but no evidence of airway inflammation.^15–19 We have shown that children with SCD have fixed but not variable airflow obstruction, and no airway inflammation, yet another sort of 'asthma'.²⁰ Depending on the ‘asthma’, the treatment should be tailored accordingly.

Although differentiating eosinophilic from non-eosinophilic disease is an essential first step, we are learning that there are more than just TH2 pathways that can cause airway eosinophilia.^{21 22} This is important, as many different biologicals are being used to target the TH2 pathway,^23–25 and in the future we will need to find ways of matching the biological to the child’s asthma, which probably means defining endotypes. The alternative is a sterile series of N of 1 trials hoping to hit on what is best for the child.

The next important area tackled is the understanding of the early evolution of the asthmas. This is particularly important if we are to move asthma treatment from mere palliative care with ICS, to prevention or cure of the disease in the early stages. A large number of birth cohort studies have provided important information about the natural history of early wheezing, but the molecular pathways are not determined, and they are not steroid responsive.^26–28 The Commission advocates moving from the reductionist approach, which has been so successful in the past, to a systems biology approach that allows a multidimensional, multilevel approach. New longitudinal studies must incorporate outcomes reflecting lung function and immunological, inflammatory, metabolic, genetic and epigenetic compartments. The profound effects of the environment on the endotypes need to be modelled, including a developmental perspective, because compartments may mature at different rates. There also needs to be an extrapulmonary focus on, for example, cardiovascular, endocrine, metabolic and neurological systems.Work published since the commission has thrown this into sharp focus; by the third decade, those in the lowest spirometry tertile have increased mortality,²⁹ probably reflecting that impaired spirometry is the ‘canary in the mine’ indicating multisystem issues.^{30 31} A step-change in our developmental perspectives is needed, with the goal being an understanding of the pathways to established eosinophilic asthma, biomarkers for those pathways and a strategy to interrupt them to prevent long-term eosinophilic inflammation^{32 33} and loss of lung function which last greatly increases the risk of adult chronic obstructive pulmonary disease (COPD).³⁴

Another crucial area is asthma attacks; the feeble word ‘exacerbation’ should not be used because it lulls people into a false sense of security. These should not be seen as a mere inconvenience, readily put right by 3–5 days of prednisolone. Rather, they are a huge sentinel event. NRAD2 has highlighted they are a risk factor for asthma deaths, and they are certainly a risk factor for further attacks. Attacks of severe wheeze in the preschool years are associated with progression to persistent wheeze, ³⁵ and attacks in the school-age years with impaired spirometry36 and thus adult COPD.³⁴ There should be zero tolerance for asthma attacks. We have much to learn from cardiology; a heart attackprompts a focused response to understand what went wrong and what future prevention steps should be taken. The same should be for lung attacks, whether due to asthma, CF^{37 38}or primary ciliary dyskinaesia, ³⁹ because they are not transient inconveniences in any of these diseases. The Commissioners also make clear the need to rethink the definition of severe asthma. NRAD highlighted that 60% of asthma deaths were in people who did not meet the current definition of severe asthma, surely a ludicrous non sequitur. The report highlighted the numerous social and environmental traits that were treatable but not addressed, in particular adherence to ICS, overuse of bronchodilators and failure to attend review appointments.2 Adherence is a particularly important aspect that the Commission discusses; we cannot rely on asking the patient-we have to use more objective measures^.40 Thus, the Commission proposes a new and broader definition of severe asthma.

Finally, the Commissioners call for better research, a cry that all paediatricians will echo. We need research in children; we cannot simply extrapolate from adults. So if we are studying early life events, we need developmentally appropriate animal models,⁴¹ sensitised appropriately (when was the last time you saw a child who had received an intraperitoneal injection of ovalbumin?). Research is an area where better phenotyping is essential. Genome-wide association studies (GWASs) and other genetic investigations are becoming ever more sophisticated, but the clinical phenotypes are often crude in the extreme -'Dr-diagnosed asthma'- we know how unreliable that is ⁴³ -or someone somewhere gave the subject an inhaler for some reason. We need to insist on better definitions of what we are actually studying. It is interesting to note that the asthma susceptibility gene CDHR3, which turns out to be the receptor for rhinovirus C, ⁴⁴ was not picked up on big GWASs of all comers with 'asthma', but only in a smaller, more focused study where the subjects had to have had an attack of acute severe wheeze ⁴⁵; was this because these subjects were actually not diluted by people with non-specific, asthma- unrelated, respiratory symptoms?

There are important implications for the delivery of care to people with asthma. Clearly, if the diagnosis is objective and secure, and the response to low-dose therapy is excellent, further testing would not be needed. However, if the response to low-dose therapy is not good, rather than sleep-walking up the steps in the guidelines, essentially giving more and more of the same therapy, we suggest that the patient ought to be seen in a specialist setting where phenotyping can be carried out, even if subsequent management is devolved back to primary care.

The Commission finishes with seven recommendations (box); it is a deliberately controversial document and meant to stimulate thought. The overall ambitious aim is to initiate a new era of personalised therapy for airway disease. We need to get the right amount of ICS to the right airways, not put steroids in the tap water; we need to make measurements, not just rely on chit-chat; and we need in all sorts of ways to move into a 21st century way of thinking about and researching airways disease. Asthma is dead—long live The Asthmas.

(Source: Bush A, Pavord ID. We can't diagnose asthma until <insert arbitrary age>'. Arch Dis Child. 2018 Aug;103(8):729-731. doi:10.1136/archdischild-2017-314180)

Seven recommendations of the Lancet commission --> Evolve from the use of umbrella terms to disease labels that allow for treatment guidelines to be more precise. What asthma do I have? --> Move beyond a disease-control approach for asthma treatment - no more 'me-too' steroids and bronchodilators. --> Emerge from age-associated and discipline-associated silos-look at the developmental trajectories of airway disease. --> Test before treatment-move away from our current 'no-test' culture. --> Zero tolerance for asthma attacks—they are not flare-ups or exacerbation, but a huge red flag. --> Make the most of new treatment opportunities in severe disease - match the biological to the endotype. --> Carry out better research—better characterisation of trial populations, better animal models.

References

1. Soto-Martínez M, Avila L, Soto N, et al. Trends in hospitalizations and mortality from asthma in Costa Rica over a 12- to 15-year period. J Allergy Clin Immunol Pract 2014;2:85–90.

2. Royol College of Physician. National review of asthma deaths. https://www. rcplondon. ac. uk/ projects/ national- review- asthma- deaths

3. Pavord ID, Beasley R, Agusti A, et al. After asthma— redefining airways diseases. A Lancet commission. Lancet 2017. Doi: 10.1016/S0140-6736(17)30879-6.[Epub ahead of print].

4. Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of chronic airway diseases.Eur Respir J 2016;47:410–9.

5. Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008;32:1096–110.

6. Brand PL, Caudri D, Eber E, et al. Classification and pharmacological treatment of preschool wheezing: changes since 2008. Eur Respir J 2014;43:1172–7.

7. Busi LE, Restuccia S, Tourres R, et al. Assessing bronchodilator response in preschool children using spirometry. Thorax 2017;72:367–72.

8. Zar HJ, Hanslo D, Apolles P, et al. Induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. Lancet 2005;365:130–4.

9. Jochmann A, Artusio L, Robson K, et al. Infection and inflammation in induced sputum from preschool children with chronic airways diseases. Pediatr Pulmonol 2016;51:778–86.

10. Lex C, Ferreira F, Zacharasiewicz A, et al. Airway eosinophilia in children with severe asthma: predictive values of noninvasive tests. Am J Respir Crit Care Med 2006;174:1286–91.

11. Fitzpatrick AM, Jackson DJ, Mauger DT, et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol 2016;138:1608–18.

12. Balfour-Lynn IM, Elborn JS. "CF asthma": what is it and what do we do about it? Thorax 2002;57:742–8. 13 Gough A, Linden M, Spence D, et al. Impaired lung function and health status in adult survivors of bronchopulmonary dysplasia. Eur Respir J 2014;43:808–16.

14. Strunk RC, Cohen RT, Cooper BP, et al. Wheezing symptoms and parental asthma are associated with a physician diagnosis of asthma in children with sickle cell anemia. J Pediatr 2014;164:821–6.15 Vollsæter M, Røksund OD, Eide GE, et al. Lung function after preterm birth: development from midchildhood to adulthood. Thorax 2013;68:767–76.

16. Brundage KL, Mohsini KG, Froese AB, et al. Bronchodilator response to ipratropium bromide in infants with bronchopulmonary dysplasia. Am Rev Respir Dis 1990;142:1137–42.

17. Baraldi E, Bonetto G, Zacchello F, et al. Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation. Am J Respir Crit Care Med 2005;171:68–72.

18. Suursalmi P, Kopeli T, Korhonen P, et al. Very low birthweight bronchopulmonary dysplasia survivors show no substantial association between lung function and current inflammatory markers. Acta Paediatr 2015;104:264–8.

19. Carraro S, Piacentini G, Lusiani M, et al. Exhaled air temperature in children with bronchopulmonary dysplasia. Pediatr Pulmonol 2010;45:1240–5.

20. Chaudry RA, Rosenthal M, Bush A, et al. Reduced forced expiratory flow but not increased exhaled nitric oxide or airway responsiveness to methacholine characterises paediatric sickle cell airway disease.Thorax 2014;69:580–5.

21. Lefaudeux D, De Meulder B, Loza MJ, et al. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. J Allergy Clin Immunol 2017;139:1797–807.

22. Wilson SJ, Ward JA, Sousa AR, et al. Severe asthma exists despite suppressed tissue inflammation: findings of the U-BIOPRED study. Eur Respir J 2016;48:1307–19.

23. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651–9.

24. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011;365:1088–98.

25. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013;368:2455–66.

26. Bisgaard H, Hermansen MN, Loland L, et al. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006;354:1998–2005.

27. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006;354:1985–97.

28. Murray CS, Woodcock A, Langley SJ, et al. Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study. Lancet 2006;368:754–62.

29. Vasquez MM, Zhou M, Hu C, et al. Low lung function in young adult life is associated with early mortality. Am J Respir Crit Care Med 2017;195:1399–401.

30. Bush A. Low lung function in young adult life is associated with early mortality. Am J Respir Crit Care Med 2017.

31. Povey H, Cameron D. The bird it was that died. Thorax 2013;68:1175.

32. Saglani S, Malmström K, Pelkonen AS, et al. Airway remodeling and inflammation in symptomatic infants with reversible airflow obstruction. Am J Respir Crit Care Med 2005;171:722–7.

33. Saglani S, Payne DN, Zhu J, et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med 2007;176:858–64.

34. Lange P, Celli B, Agustí A, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 2015;373:111–22.

35. Belgrave DC, Buchan I, Bishop C, et al. Trajectories of lung function during childhood. Am J Respir Crit Care Med 2014;189:1101–9.

36. O'Byrne PM, Pedersen S, Lamm CJ, et al. Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med 2009;179:19–24.

37. Sanders DB, Bittner RC, Rosenfeld M, et al. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med 2010;182:627–32.

38. de Boer K, Vandemheen KL, Tullis E, et al. Exacerbation frequency and clinical outcomes in adult patients with cystic fibrosis. Thorax 2011;66:680–5.

39. Sunther M, Bush A, Hogg C, et al. Recovery of baseline lung function after pulmonary exacerbation in children with primary ciliary dyskinesia. Pediatr Pulmonol 2016;51:1362–6.

40. Sulaiman I, Seheult J, MacHale E, et al. A method to calculate adherence to inhaled therapy that reflects the changes in clinical features of asthma. Ann Am Thorac Soc 2016;13:1894–903.

41. Saglani S, Mathie SA, Gregory LG, et al. Pathophysiological features of asthma develop in parallel in house dust mite-exposed neonatal mice. Am J Respir Cell Mol Biol 2009;41:281–9.

42. Looijmans-van den Akker I, van Luijn K, Verheij T. Overdiagnosis of asthma in children in primary care: a retrospective analysis. Br J Gen Pract 2016;66:e152–e157.

43. Aaron SD, Vandemheen KL, FitzGerald JM, et al. Canadian Respiratory Research Network. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA 2017;317:269–79.

44. Bochkov YA, Watters K, Ashraf S, et al. Cadherinrelated family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication. Proc Natl Acad Sci U S A 2015;112:5485–90.

45. Bønnelykke K, Sleiman P, Nielsen K, et al. A genomewide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet 2014;46:51–5