Clinically accessible biomarkers to assess the modifiable risk of asthma/wheezing attacks in toddlers

We read with interest the work by Fitzpatrick et al1Fitzpatrick A.M. Grunwell J.R. Cottrill K.A. Mutic A.D. Mauger D.T. Blood eosinophils for prediction of exacerbation in preschool children with recurrent wheezing.J Allergy Clin Immunol Pract. 2023; 11: 1485-1493Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar on the prognostic and theragnostic value of blood eosinophils in pediatric asthma. In their post hoc analysis of three randomized controlled trials, the authors combined patients of all treatment arms to deliver a biomarker-stratified analysis of asthma attack occurrence according to the baseline blood eosinophil count. The analysis, conducted in 1,074 toddlers (12- to 71-month-olds) with recurrent wheezing, showed a higher risk for wheezing episodes requiring rescue systemic corticosteroids or hospitalization with increasing blood eosinophil counts. Sensitization to one or multiple allergens was associated with 54% to 92% increased odds of exacerbations requiring rescue systemic corticosteroids, compared with none. The prognostic value of blood eosinophils was enhanced when associated with atopic sensitization, particularly food sensitization. Finally, using the single trial with FeNO measurements (CARE-MIST), the authors report that reductions in FeNO were greater with maintenance than with intermittent inhaled corticosteroids, but did not report the prognostic and theragnostic value of FeNO. It struck us that the observations of Fitzpatrick et al1Fitzpatrick A.M. Grunwell J.R. Cottrill K.A. Mutic A.D. Mauger D.T. Blood eosinophils for prediction of exacerbation in preschool children with recurrent wheezing.J Allergy Clin Immunol Pract. 2023; 11: 1485-1493Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar regarding the modifiable risk for wheezing episodes conferred by raised blood eosinophil counts in these pediatric trials are concordant with those observed in school-age children, adolescents, and adults with asthma of any severity (aged 6 to less than 12 years2Bacharier L. Jackson D. Pavord I. Maspero J. Mao X. Liu D. et al.Efficacy of dupilumab in quadrants of elevated- vs low- type 2 biomarkers in children with uncontrolled, moderate-to-severe asthma: LIBERTY ASTHMA VOYAGE.J Allergy Clin Immunol. 2022; 149: AB18Abstract Full Text Full Text PDF Google Scholar and aged 12 years and older3Couillard S. Laugerud A. Jabeen M. Ramakrishnan S. Melhorn J. Hinks T.S.C. et al.Derivation of a prototype asthma attack risk scale centred on blood eosinophils and exhaled nitric oxide.Thorax. 2022; 77: 199-202Crossref PubMed Scopus (40) Google Scholar,4Couillard S. Do W. Beasley R. Hinks T. Pavord I. Predicting the benefits of type-2 targeted anti-inflammatory treatment with the prototype OxfoRd Asthma attaCk risk scaLE (ORACLE).ERJ Open Res. 2022; 8: 1-5Crossref Scopus (0) Google Scholar). Considering the established association between FeNO and the number of sensitizations,5Jackson D.J. Virnig C.M. Gangnon R.E. Evans M.D. Roberg K.A. Anderson E.L. et al.Fractional exhaled nitric oxide measurements are most closely associated with allergic sensitization in school-age children.J Allergy Clin Immunol. 2009; 124 (949-3)Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar it is likely that the study population's toddlers with a greater number of sensitizations also would have had a raised FeNO. We note the absence of a predictive/responder analysis using combinations of blood eosinophils and FeNO in the report, but we understand that this would have been underpowered. Nevertheless, it would have been interesting to show the attack rates of the two treatment arms in CARE-MIST stratified by blood eosinophils and FeNO quadrants, similar to the post hoc analysis of the VOYAGE trial in 6- to less than 12-year-olds with moderate to severe asthma. In VOYAGE, placebo-treated children with higher baseline blood eosinophils and FeNO (≥0.15 × 109/L and ≥20 parts per billion (ppb), respectively) had a sixfold increase in adjusted annualized asthma attack rates compared with those with low-low biomarker values (<0.15 × 109/L and 20 ppb): 0.82 versus 0.13 attacks/y. Moreover, children with high-high baseline biomarkers showed the greatest relative and absolute treatment effects of type 2 targeting anti-inflammatory therapy compared with placebo, and those with low-low values showed no effect: ↓65% (–0.53 attacks/y) versus +35% (+0.04 attacks/y).2Bacharier L. Jackson D. Pavord I. Maspero J. Mao X. Liu D. et al.Efficacy of dupilumab in quadrants of elevated- vs low- type 2 biomarkers in children with uncontrolled, moderate-to-severe asthma: LIBERTY ASTHMA VOYAGE.J Allergy Clin Immunol. 2022; 149: AB18Abstract Full Text Full Text PDF Google Scholar FeNO may have additive value to the blood eosinophil count with regard to the prediction of asthma attacks with placebo and the likelihood of treatment response with type 2 targeting anti-inflammatory therapy. Were these results also seen in the trial population of toddlers in Fitzpatrick et al1Fitzpatrick A.M. Grunwell J.R. Cottrill K.A. Mutic A.D. Mauger D.T. Blood eosinophils for prediction of exacerbation in preschool children with recurrent wheezing.J Allergy Clin Immunol Pract. 2023; 11: 1485-1493Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar who had blood eosinophils and FeNO measured? Differences between children and adults with regard to the modifiable risk posed by type 2 inflammation seem to be minimal. Indeed, the results of the VOYAGE biomarker-stratified analysis are similar to those observed in adults, with the exception of a greater prognostic and theragnostic value of FeNO in children with low blood eosinophils.2Bacharier L. Jackson D. Pavord I. Maspero J. Mao X. Liu D. et al.Efficacy of dupilumab in quadrants of elevated- vs low- type 2 biomarkers in children with uncontrolled, moderate-to-severe asthma: LIBERTY ASTHMA VOYAGE.J Allergy Clin Immunol. 2022; 149: AB18Abstract Full Text Full Text PDF Google Scholar We suggested that blood eosinophils and FeNO identify an abnormal inflammatory process in the systemic and airway compartments, respectively.6Couillard S. Shrimanker R. Chaudhuri R. Mansur A.H. McGarvey L.P. Heaney L.G. et al.Fractional exhaled nitric oxide nonsuppression identifies corticosteroid-resistant type 2 signaling in severe asthma.Am J Respir Crit Care Med. 2021; 204: 731-734Crossref PubMed Scopus (29) Google Scholar Therefore, children with asthma may have more epithelial/atopic-driven type 2 inflammation and would benefit more from anti-inflammatory therapies directed toward that process.7Bush A. Differing effects of mepolizumab across the life course.Lancet Respir Med. 2023; 11: 123-125Abstract Full Text Full Text PDF PubMed Google Scholar There is a growing case for an asthma attack risk scale based on the additive prognostic and theragnostic value of clinically accessible biomarkers across asthma severities.3Couillard S. Laugerud A. Jabeen M. Ramakrishnan S. Melhorn J. Hinks T.S.C. et al.Derivation of a prototype asthma attack risk scale centred on blood eosinophils and exhaled nitric oxide.Thorax. 2022; 77: 199-202Crossref PubMed Scopus (40) Google Scholar,4Couillard S. Do W. Beasley R. Hinks T. Pavord I. Predicting the benefits of type-2 targeted anti-inflammatory treatment with the prototype OxfoRd Asthma attaCk risk scaLE (ORACLE).ERJ Open Res. 2022; 8: 1-5Crossref Scopus (0) Google Scholar The results of the research by Fitzpatrick et al1Fitzpatrick A.M. Grunwell J.R. Cottrill K.A. Mutic A.D. Mauger D.T. Blood eosinophils for prediction of exacerbation in preschool children with recurrent wheezing.J Allergy Clin Immunol Pract. 2023; 11: 1485-1493Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and VOYAGE2Bacharier L. Jackson D. Pavord I. Maspero J. Mao X. Liu D. et al.Efficacy of dupilumab in quadrants of elevated- vs low- type 2 biomarkers in children with uncontrolled, moderate-to-severe asthma: LIBERTY ASTHMA VOYAGE.J Allergy Clin Immunol. 2022; 149: AB18Abstract Full Text Full Text PDF Google Scholar suggest a potential utility for stratifying risk plus treatment opportunities by blood eosinophils and other clinically accessible biomarkers, including atopic sensitization when FeNO is not feasible. Blood Eosinophils for Prediction of Exacerbation in Preschool Children With Recurrent WheezingThe Journal of Allergy and Clinical Immunology: In PracticeVol. 11Issue 5PreviewAlthough clinical features of type 2 inflammation have been associated with poorer longitudinal outcomes in preschool children with recurrent wheezing, it remains difficult to predict which children are at highest risk for poor outcomes during a routine clinical encounter. Full-Text PDF Reply to “Clinically accessible biomarkers to assess the modifiable risk of asthma/wheezing attacks in toddlers”The Journal of Allergy and Clinical Immunology: In PracticeVol. 11Issue 6PreviewCouillard and colleagues1 raise important and interesting questions about the utility of FeNO measurements in detecting the risk for future asthma and/or wheezing exacerbations in preschool children. Our recent analysis2 demonstrated that elevated blood eosinophil cut points in preschool children, particularly when combined with sensitization variables, were associated with higher exacerbation rates and improved responses to initiation of daily inhaled corticosteroid (ICS) treatment in exploratory analyses. Full-Text PDF