Skip to main content
SpringerLink
Log in

Small Airway Disease in Pediatric Asthma: the Who, What, When, Where, Why, and How to Remediate. A Review and Commentary

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Asthma affects all portions of the airways. Small airways, however, comprise a substantial component of the conducting lung air flow. In asthma, inflammatory processes can affect the whole respiratory tract, from central to peripheral/small airways. The emphasis in adult and pediatric respiratory disease clinics is to focus on large airway obstruction and reversibility. This information, although valuable, underemphasizes a large portion of the conduction airway of asthmatics. Standard descriptions of asthma management focus on a multiple medication approaches. We particularly focused on the management of asthma in the international guidelines for the Global Initiative for Asthma (GINA). Overall, however, minimal attention is placed on the small airway pool in asthma medical management. We took the opportunity to thoroughly review and present specific data from the adult asthma literature which supported the concept that small airway abnormalities may play a role in the pathogenesis and clinical expression of asthma. Based on the conclusions of the adult asthma literature, we here present a thorough review of the literature as it relates to small airway disease in children with asthma. We used, collectively, individual data sources of data to expand the information available from standard diagnostic techniques, especially spirometry, in the evaluation of small airway disease. As the pharmacological approaches to moderate to severe asthma are advancing rapidly into the realm of biologics, we sought to present potential pharmacological options for small airway dysfunction in pediatrics prior to biological modifier intervention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

SAD:

Small airway disease (dysfunction)

GINA:

Global Initative for Asthma

FeNO:

Fractional expired nitric oxide

IOS:

Impulse oscillometry

FVC:

Forced vital capacity

FEV1:

Forced expiratory flow at 1 sec

FEF25-75:

Forced expiratory flow at 25–75 of forced vital capacity

FEF50:

Forced expiratory flow at 50% of forced vital capacity

R5-R20:

Measurement of respiratory resistance between R5 and R20

AX:

Area of reactance. X5: Represents the reactance throughout the respiratory system

RV:

Residual volume

TLC:

Total lung capacity

ICS:

Inhaled corticosteroid

(CalvNO):

Calculated alveolar nitric oxide

FEVz:

Z score for FEV1

sRawz:

Z score for specific airway conductance

MMEFz:

Z score for mid-maximal expiratory flow

AIT:

Allergy immunotherapy

LABA:

Long-acting beta-agonist

LAMA:

Long-acting muscarinic antagonist

ACT:

Asthma control test scores

CASI:

Composite asthma severity index

References

  1. Staub NC, Albertine KH (1988) Structure of the lungs relative to their principal function. In: Murray JF, Nadel JA (eds) Textbook of Respiratory Medicine, 1st edn. W.B. Saunders, Philadelphia, pp 15–20

    Google Scholar 

  2. Bosse Y, Riesenfeld EP, Pare PD, Irvin CG (2010) It’s not all smooth muscle: non-smooth-muscle elements in control of resistance to airflow. Annu Rev Physiol 72:437–462

    CAS  PubMed  Google Scholar 

  3. Gold DR, Sordillo JE, Coull BA (2020) Lung function tracking throughout childhood: growth trajectories May Not Be Set in Stone. J Allergy Clin Immunol Pract 8:1272–1274

    PubMed  Google Scholar 

  4. Cottini M, Licini A, Lombardi C, Berti A (2020) Clinical characterization and predictors of IOS-defined small-airway dysfunction in asthma. J Allergy Clin Immunol Pract 8:997,1004.e2. https://doi.org/10.1016/j.jaip.2019.10.040

    Article  Google Scholar 

  5. Cottini M, Lombardi C, Micheletto C (2015) Small airway dysfunction and bronchial asthma control: the state of the art. Asthma Res Pract. https://doi.org/10.1186/s40733-015-0013-3

  6. Burgel PR (2011) The role of small airways in obstructive airway diseases. Eur Respir Rev 20:23–33. https://doi.org/10.1183/09059180.00010410

    Article  PubMed  Google Scholar 

  7. van der Wiel E, ten Hacken NH, Postma DS, van den Berge M (2013) Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: a systematic review. J Allergy Clin Immunol 131:646–657

    PubMed  Google Scholar 

  8. Knihtila H, Kotaniemi-Syrjanen A, Pelkonen AS, Makela MJ, Malmberg LP (2018) Small airway function in children with mild to moderate asthmatic symptoms. Ann Allergy Asthma Immunol 121:451–457

    PubMed  Google Scholar 

  9. Knihtila H, Kotaniemi-Syrjanen A, Pelkonen AS, Kalliola S, Makela MJ, Malmberg LP (2017) Small airway oscillometry indices: repeatability and bronchodilator responsiveness in young children. Pediatr Pulmonol 52:1260–1267

    PubMed  Google Scholar 

  10. Keen C, Olin AC, Wennergren G, Gustafsson P (2011) Small airway function, exhaled NO and airway hyper-responsiveness in paediatric asthma. Respir Med 105:1476–1484

    PubMed  Google Scholar 

  11. Singer F, Abbas C, Yammine S, Casaulta C, Frey U, Latzin P (2014) Abnormal small airways function in children with mild asthma. Chest. 145:492–499

    PubMed  Google Scholar 

  12. Hill DJ, Landau LI, McNicol KN, Phelan PD (1972) Asthma--the physiological and clinical spectrum in childhood. Respiratory function studies in its assessment. Arch Dis Child 47:874–881

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Tirakitsoontorn P, Crookes M, Fregeau W, Pabelonio N, Morphew T, Shin HW et al (2108) Recognition of the peripheral airway impairment phenotype in children with well-controlled asthma. Ann Allergy Asthma Immunol 121(6):692–698

    Google Scholar 

  14. Hill DJ, Landau LI, Phelan PD (1972) Small airway disease in asymptomatic asthmatic adolescents. Am Rev Respir Dis 106:873–880

    CAS  PubMed  Google Scholar 

  15. Mead J (1970) The lung’s “quiet zone”. N Engl J Med 282(23):1318–1319

    CAS  PubMed  Google Scholar 

  16. Landau LI, Mellis CM, Phelan PD, Bristowe B, McLennan L (1979) “Small airways disease” in children: no test is best. Thorax. 134:217–223

    Google Scholar 

  17. Saetta M, Turato G (2001) Airway pathology in asthma. Eur Respir J 34:18s–23s

    CAS  Google Scholar 

  18. Hafez MR, Abu-Bakr SM, Mohamed AA (2015) Forced oscillometry track sites of airway obstruction in bronchial asthma. Ann Allergy Asthma Immunol 115:28–32

    PubMed  Google Scholar 

  19. Macklem PT (1998) The physiology of small airways. Am J Respir Crit Care 157:S181–S183

    CAS  Google Scholar 

  20. Macklem PT, Mead J (1967) Resistance of central and peripheral airways measured by a retrograde catheter. J Appl Physiol 22:395–401

    CAS  PubMed  Google Scholar 

  21. Hogg JC, Macklem PT, Thurlbeck WM (1968) Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 278:1355–1360

    CAS  PubMed  Google Scholar 

  22. Hogg JC, Williams J, Richardson JB, Macklem PT, Thurlbeck WM (1970) Age as a factor in the distribution of lower-airway conductance and in the pathologic anatomy of obstructive lung disease. N Engl J Med 282:1283–1287

    CAS  PubMed  Google Scholar 

  23. 2020 GINA Main Report 2020. https://ginasthma.org/gina-reports/. Accessed Sept 15, 2020

  24. Smith BM, Kirby M, Hoffman EA, Kronmal RA, Aaron SD, Allen NB et al (2020) Association of dysanapsis with chronic obstructive pulmonary disease among older adults. JAMA. 323:2268–2280

    PubMed  PubMed Central  Google Scholar 

  25. Forno E, Weiner DJ, Mullen J, Sawicki G, Kurland G, Han YY et al (2017) Obesity and airway dysanapsis in children with and without asthma. Am J Respir Crit Care Med 195:314–323

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Usmani OS, Singh D, Spinola M, Bizzi A, Barnes PJ (2016) The prevalence of small airways disease in adult asthma: a systematic literature review. Respir Med 116:19–27

    PubMed  Google Scholar 

  27. Carr TF, Altisheh R, Zitt M (2017) Small airways disease and severe asthma. World Allergy Organ J 10(1):20. https://doi.org/10.1186/s40413-017-0153-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Coverstone AM, Seibold MA, Peters MC (2020) Diagnosis and management of T2-high asthma. J Allergy Clin Immunol Pract 8:442–450

    PubMed  Google Scholar 

  29. Fitzpatrick AM, Chipps BE, Holguin F, Woodruff PG (2020) T2-"low" asthma: overview and management strategies. J Allergy Clin Immunol Pract 8:452–463

    PubMed  Google Scholar 

  30. Hopp R (2020) Hypersensitivity reactions: an everyday occurrence in pediatric allergy clinics. Pediatr Allergy Immunol Pulmonol 33:12–18

    PubMed  PubMed Central  Google Scholar 

  31. Saglani S, Custovic A (2019) Childhood asthma: advances using machine learning and mechanistic studies. Am J Respir Crit Care Med 199:414–422

    CAS  PubMed  Google Scholar 

  32. Lipworth B, Manoharan A, Anderson W (2014) Unlocking the quiet zone: the small airway asthma phenotype. Lancet Respir Med 2:497–506

    PubMed  Google Scholar 

  33. Telenga ED, van den Berge M, Ten Hacken NH, Riemersma RA, van der Molen T, Postma DS (2013) Small airways in asthma: their independent contribution to the severity of hyperresponsiveness. Eur Respir J 41:752–754

    CAS  PubMed  Google Scholar 

  34. Pavord ID, Beasley R, Agusti A, Anderson GP, Bel E, Brusselle G et al (2018) After asthma: redefining airways diseases. Lancet. 391:350–400. https://doi.org/10.1016/S0140-6736(17)30879-6

    Article  PubMed  Google Scholar 

  35. Szefler SJ (2018) Asthma across the lifespan: time for a paradigm shift. J Allergy Clin Immunol 142:773–780

    PubMed  Google Scholar 

  36. Panettieri RA Jr, Covar R, Grant E, Hillyer EV, Bacharier L (2008) Natural history of asthma: persistence versus progression-does the beginning predict the end? J Allergy Clin Immunol 121:607–613

    PubMed  Google Scholar 

  37. Lanz MJ, Gilbert I, Szefler SJ, Murphy KR (2019) Can early intervention in pediatric asthma improve long-term outcomes? A question that needs an answer. Pediatr Pulmonol 54:348–357

    PubMed  PubMed Central  Google Scholar 

  38. McGeachie MJ (2017) Childhood asthma is a risk factor for the development of chronic obstructive pulmonary disease. Curr Opin Allergy Clin Immunol 17:104–109

    PubMed  PubMed Central  Google Scholar 

  39. McGeachie MJ, Yates KP, Zhou X, Guo F, Sternberg AL, Van Natta ML et al (2016) Patterns of growth and decline in lung function in persistent childhood asthma. N Engl J Med 374:1842–1852

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Subbarao P (2019) The final frontier: preschool asthma severity-the silent years no more. Ann Am Thorac Soc 16:550–552

    PubMed  Google Scholar 

  41. Zinellu E, Piras B, Ruzittu GGM, Fois SS, Fois AG, Pirina P (2019) Recent advances in inflammation and treatment of small airways in asthma. Int J Mol Sci. https://doi.org/10.3390/ijms20112617

  42. Vieira Braga FA, Kar G, Berg M, Carpaij OA, Polanski K, Simon LM et al (2019) A cellular census of human lungs identifies novel cell states in health and in asthma. Nat Med 25:1153–1163

    CAS  PubMed  Google Scholar 

  43. Postma DS, Brightling C, Baldi S, Van den Berge M, Fabbri LM, Gagnatelli A et al (2019) Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort study. Lancet Respir Med 2019(7):402–416

    Google Scholar 

  44. Sorkness RL, Zoratti EM, Kattan M, Gergen PJ, Evans MD, Visness CM et al (2018) Obstruction phenotype as a predictor of asthma severity and instability in children. J Allergy Clin Immunol 142:1090–1099. https://doi.org/10.1016/j.jaci.2017.09.047

    Article  PubMed  Google Scholar 

  45. Simon MR, Chinchilli VM, Phillips BR, Sorkness CA, Lemanske RF Jr, Szefler SJ et al (2010) Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV1 values. J Allergy Clin Immunol 126:527–534

    PubMed  PubMed Central  Google Scholar 

  46. Francisco B, Ner Z, Ge B, Hewett J, Konig P (2015) Sensitivity of different spirometric tests for detecting airway obstruction in childhood asthma. J Asthma 52:505–511

    PubMed  Google Scholar 

  47. McNulty W, Usmani OS (2014) Techniques of assessing small airways dysfunction. Eur Clin Respir J 1. https://doi.org/10.3402/ecrj.v1.25898 eCollection 2014

  48. de Blic J, Scheinmann P (2007) The use of imaging techniques for assessing severe childhood asthma. J Allergy Clin Immunol 119:808–810

    PubMed  Google Scholar 

  49. Komarow HD, Myles IA, Uzzaman A, Metcalfe DD (2011) Impulse oscillometry in the evaluation of diseases of the airways in children. Ann Allergy Asthma Immunol 106:191–199

    PubMed  PubMed Central  Google Scholar 

  50. Chipps BE, Bacharier LB, Farrar JR, Jackson DJ, Murphy KR, Phipatanakul W et al (2018) The pediatric asthma yardstick: practical recommendations for a sustained step-up in asthma therapy for children with inadequately controlled asthma. Ann Allergy Asthma Immunol 120:559–579. https://doi.org/10.1016/j.anai.2018.04.002

    Article  PubMed  Google Scholar 

  51. Pavord I, Bahmer T, Braido F, Cosio BG, Humbert M, Idzko M et al (2019) Severe T2-high asthma in the biologics era: European experts’ opinion. Eur Respir Rev 28:190054. https://doi.org/10.1183/16000617.0054-2019

    Article  PubMed  Google Scholar 

  52. Expert Panel Report 4 (EPR-4) Working Group (2018) https://www.nhlbi.nih.gov/about/advisory-and-peer-review-committees/national-asthma-education-and-prevention-program-coordinating/EPR4-working-group. Accessed Sept 15, 2020

  53. Hew M, Menzies-Gow A, Hull JH, Fleming L, Porsberg C et al (2020) Systematic assessment of difficult-to-treat asthma: principles and perspectives. J Allergy Clin Immunol Pract 8(7):2222–2233. https://doi.org/10.1016/j.jaip.2020.02.036

    Article  PubMed  Google Scholar 

  54. Hallas HW, Chawes BL, Arianto L, Rasmussen MA, Kunoe A, Stokholm J et al (2020) Children with asthma have fixed airway obstruction through childhood unaffected by exacerbations. J Allergy Clin Immunol Pract 8:1263–1271. https://doi.org/10.1016/j.jaip.2019.10.031

    Article  PubMed  Google Scholar 

  55. Hallas HW, Chawes BL, Rasmussen MA, Arianto L, Stokholm J, Bonnelykke K et al (2019) Airway obstruction and bronchial reactivity from age 1 month until 13 years in children with asthma: a prospective birth cohort study. PLoS Med 16:e1002722. https://doi.org/10.1371/journal.pmed.1002722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Guerra S, Lombardi E, Stern DA, Sherrill DL, Gilbertson-Dahdal D, Wheatley-Guy CM et al (2020) Fetal origins of asthma: a longitudinal study from birth to age 36 years. Am J Respir Crit Care Med. https://doi.org/10.1164/rccm.202001-0194OC

  57. Hopp RJ, Pasha MA (2016) A literature review of the evidence that a 12% improvement in FEV1 is an appropriate cut-off for children. J Asthma 53:413–418

    PubMed  Google Scholar 

  58. Galant SP, Fregeau W, Pabelonio N, Morphew T, Tirakitsoontorn P (2020) Standardized IOS reference values define peripheral airway impairment-associated uncontrolled asthma risk across ethnicity in children. J Allergy Clin Immunol Pract 8:2698–2706. https://doi.org/10.1016/j.jaip.2020.03.040

    Article  PubMed  Google Scholar 

  59. Taylor DR, Pijnenburg MW, Smith AD, De Jongste JC (2006) Exhaled nitric oxide measurements: clinical application and interpretation. Thorax. 61:817–827

    CAS  PubMed  PubMed Central  Google Scholar 

  60. van den Berge M, ten Hacken NH, van der Wiel E, Postma DS (2013) Treatment of the bronchial tree from beginning to end: targeting small airway inflammation in asthma. Allergy. 68:16–26

    PubMed  Google Scholar 

  61. Usmani OS (2014) Small airways dysfunction in asthma: evaluation and management to improve asthma control. Allergy, Asthma Immunol Res 6:376–388

    CAS  Google Scholar 

  62. Peters U, Dixon AE, Forno E (2018) Obesity and asthma. J Allergy Clin Immunol 141:1169–1179

    PubMed  PubMed Central  Google Scholar 

  63. Holguin F, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Erzurum SC et al (2011) Obesity and asthma: an association modified by age of asthma onset. J Allergy Clin Immunol 127:1486–1493

    PubMed  PubMed Central  Google Scholar 

  64. Teague WG, Lawrence MG, Shirley DT, Garrod AS, Early SV, Payne JB et al (2019) Lung lavage granulocyte patterns and clinical phenotypes in children with severe, therapy-resistant asthma. J Allergy Clin Immunol Pract 7:1803–1812. https://doi.org/10.1016/j.jaip.2018.12.027

    Article  PubMed  PubMed Central  Google Scholar 

  65. Barsky EE, Giancola LM, Baxi SN, Gaffin JM (2018) A practical approach to severe asthma in children. Ann Am Thorac Soc 15:399–408

    PubMed  PubMed Central  Google Scholar 

  66. Foy BH, Soares M, Bordas R, Richardson M, Bell A, Singapuri A et al (2019) Lung computational models and the role of the small airways in asthma. Am J Respir Crit Care Med 200:982–991

    PubMed  PubMed Central  Google Scholar 

  67. Sheehan WJ, Phipatanakul W (2016) Indoor allergen exposure and asthma outcomes. Curr Opin Pediatr 28:772–777

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Greenberger PA (2019) Lessons learned from clinical trials of asthma. Allergy Asthma Proc 40:410–413

    CAS  PubMed  Google Scholar 

  69. Gautier C, Charpin D (2017) Environmental triggers and avoidance in the management of asthma. J Asthma Allergy 10:47–56

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Diette GB, McCormack MC, Hansel NN, Breysse PN, Matsui EC (2008) Environmental issues in managing asthma. Respir Care 53(5):602–617

    PubMed  Google Scholar 

  71. Matsui EC, Abramson SL, Sandel MT (2016) SECTION ON ALLERGY AND IMMUNOLOGY, COUNCIL ON ENVIRONMENTAL HEALTH. Indoor environmental control practices and asthma management. Pediatrics. 138:e20162589. https://doi.org/10.1542/peds.2016-2589

    Article  PubMed  Google Scholar 

  72. Hauptman M, Gaffin JM, Petty CR, Sheehan WJ, Lai PS, Coull B et al (2020) Proximity to major roadways and asthma symptoms in the school inner-city asthma study. J Allergy Clin Immunol 145:119–126.e4. https://doi.org/10.1016/j.jaci.2019.08.038

    Article  PubMed  Google Scholar 

  73. Rehman N, Morais-Almeida M, Chen A (2020) Asthma across childhood: improving adherence to asthma management from early childhood to adolescence. J Allergy Clin Immunol Pract 8:1802–1807. https://doi.org/10.1016/j.jaip.2020.02.011

    Article  PubMed  PubMed Central  Google Scholar 

  74. Cui X, Li Z, Teng Y, Barkjohn KK, Norris CL, Fang L et al (2020) Association between bedroom particulate matter filtration and changes in airway pathophysiology in children with asthma. JAMA Pediatr 174:533–542. https://doi.org/10.1001/jamapediatrics.2020.0140

    Article  PubMed  PubMed Central  Google Scholar 

  75. Levy ML, Dekhuijzen PN, Barnes PJ, Broeders M, Corrigan CJ, Chawes BL et al (2016) Inhaler technique: facts and fantasies. A view from the aerosol drug management improvement team (ADMIT). NPJ Prim Care Respir Med 26:16017. https://doi.org/10.1038/npjpcrm.2016.17

    Article  PubMed  PubMed Central  Google Scholar 

  76. American Academy of Pediatrics. Five things physicians and patients should question. https://www.choosingwisely.org/societies/american-academy-of-pediatrics-section-on-pediatric-pulmonology-and-sleep-medicine Accessed Sept 15, 2020

  77. Liu J, Dong YQ, Yin J, Yao J, Shen J, Sheng GJ et al (2019) Meta-analysis of vitamin D and lung function in patients with asthma. Respir Res 20:Article number 161. https://doi.org/10.1186/s12931-019-1072-4

    Article  CAS  Google Scholar 

  78. Martineau AR, Cates CJ, Urashima M, Jensen M, Griffiths AP, Nurmatov U, et al (2016) Vitamin D for the management of asthma. Cochrane Database Syst Rev https://doi.org/10.1002/14651858.CD011511.pub2/full

  79. Fares MM, Alkhaled LH, Mroueh SM, Akl EA (2015) Vitamin D supplementation in children with asthma: a systematic review and meta-analysis. BMC Res Notes 8:23. https://doi.org/10.1186/s13104-014-0961-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Brehm JM, Celedon JC, Soto-Quiros ME, Avila L, Hunninghake GM, Forno E et al (2009) Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med 179:765–771

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Brehm JM, Schuemann B, Fuhlbrigge AL, Hollis BW, Strunk RC, Zeiger RS et al (2010) Serum vitamin D levels and severe asthma exacerbations in the childhood asthma management program study. J Allergy Clin Immunol 126(1):52–58

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Black PN, Scragg R (2005) Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest. 128:3792–3798. https://doi.org/10.1378/chest.128.6.3792

    Article  CAS  PubMed  Google Scholar 

  83. Lewis E, Fernandez C, Nella A, Hopp R, Gallagher JC, Casale TB (2012) Relationship of 25-hydroxyvitamin D and asthma control in children. Ann Allergy Asthma Immunol 108(4):281–282. https://doi.org/10.1016/j.anai.2012.01.003

    Article  PubMed  Google Scholar 

  84. Forno E, Bacharier LB, Phipatanakul W, Guilbert TW, Cabana MD et al (2020) Effect of vitamin D3 supplementation on severe asthma exacerbations in children with asthma and low vitamin D levels: the VDKA randomized clinical trial. JAMA 324:752–760. https://doi.org/10.1001/jama.2020.12384

    Article  CAS  PubMed  Google Scholar 

  85. Zhang Z, Shi L, Pang W, Liu W, Li J, Wang H et al (2016) Dietary fiber intake regulates intestinal microflora and inhibits ovalbumin-induced allergic airway inflammation in a mouse model. PLoS One 11:e0147778. https://doi.org/10.1371/journal.pone.0147778 eCollection 2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Folkerts J, Stadhouders R, Redegeld FA, Tam SY, Hendriks RW, Galli SJ et al (2018) Effect of dietary fiber and metabolites on mast cell activation and mast cell-associated diseases. Front Immunol 29(9):1067. https://doi.org/10.3389/fimmu.2018.01067 eCollection 2018

    Article  CAS  Google Scholar 

  87. Perdijk O, Marsland BJ (2019) The microbiome: toward preventing allergies and asthma by nutritional intervention. Curr Opin Immunol 60:10–18. https://doi.org/10.1016/j.coi.2019.04.001

    Article  CAS  PubMed  Google Scholar 

  88. Barcik W, Boutin RCT, Sokolowska M, Finlay BB (2020) The role of lung and gut microbiota in the pathology of asthma. Immunity. 52:241–255. https://doi.org/10.1016/j.immuni.2020.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Halnes I, Baines KJ, Berthon BS, MacDonald-Wicks LK, Gibson PG, Wood LG (2017) Soluble fibre meal challenge reduces airway inflammation and expression of GPR43 and GPR41 in asthma. Nutrients 9:57. https://doi.org/10.3390/nu9010057

    Article  CAS  PubMed Central  Google Scholar 

  90. Saeed MA, Gribben KC, Alam M, Lyden ER, Hanson CK, LeVan TD Association of dietary fiber on asthma, respiratory symptoms, and inflammation in the adult national health and nutrition examination survey population. Ann Am Thorac 9:1062–1068. https://doi.org/10.1513/AnnalsATS.201910-776OC

  91. Tobias TAM, Wood LG, Rastogi D (2019) Carotenoids, fatty acids and disease burden in obese minority adolescents with asthma. Clin Exp Allergy 49:838–846

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Guilleminault L, Williams EJ, Scott HA, Berthon BS, Jensen M, Wood LG (2017) Diet and asthma: is it time to adapt our message? Nutrients 9:1227. https://doi.org/10.3390/nu9111227

    Article  CAS  PubMed Central  Google Scholar 

  93. Wood LG (2017) Diet, obesity, and asthma. Ann Am Thorac Soc 14(Supplement 5):S332–S338. https://doi.org/10.1513/AnnalsATS.201702-124AW

    Article  PubMed  Google Scholar 

  94. McLoughlin RF, Berthon BS, Wood LG (2020) Weight loss in obese children with asthma - is it important? Paediatr Respir Rev. https://doi.org/10.1016/j.prrv.2020.02.007

  95. Scott HA, Wood LG, Gibson PG (2017) Role of obesity in asthma: mechanisms and management strategies. Curr Allergy Asthma Rep 17(8):53. https://doi.org/10.1007/s11882-017-0719-9

    Article  PubMed  Google Scholar 

  96. Jay M, Wijetunga NA, Stepney C, Dorsey K, Chua DM, Bruzzese JM (2012) The relationship between asthma and obesity in urban early adolescents. Pediatr Allergy Immunol Pulmonol 25:159–167

    PubMed  PubMed Central  Google Scholar 

  97. Randolph C (2019) Being overweight or obese and the development of asthma. Pediatrics 144(Supplement 1):S42–S43. https://doi.org/10.1542/peds.2019-2461LL

    Article  Google Scholar 

  98. Chen YC, Dong GH, Lin KC, Lee YL (2013) Gender difference of childhood overweight and obesity in predicting the risk of incident asthma: a systematic review and meta-analysis. Obes Rev 14:222–231. https://doi.org/10.1111/j.1467-789X.2012.01055.x

    Article  CAS  PubMed  Google Scholar 

  99. Vo P, Makker K, Matta-Arroyo E, Hall CB, Arens R, Rastogi D (2013) The association of overweight and obesity with spirometric values in minority children referred for asthma evaluation. J Asthma 50:56–63

    PubMed  Google Scholar 

  100. Ulrik CS (2016) Asthma and obesity: is weight reduction the key to achieve asthma control? Curr Opin Pulm Med 22:69–73

    CAS  PubMed  Google Scholar 

  101. Dias-Junior SA, Reis M, de Carvalho-Pinto RM, Stelmach R, Halpern A, Cukier A (2014) Effects of weight loss on asthma control in obese patients with severe asthma. Eur Respir J 43:1368–1377

    CAS  PubMed  Google Scholar 

  102. Khan UI, Rastogi D, Isasi CR, Coupey SM (2012) Independent and synergistic associations of asthma and obesity with systemic inflammation in adolescents. J Asthma 49:1044–1050

    PubMed  Google Scholar 

  103. Arron JR, Choy DF, Scheerens H, Matthews JG (2013) Noninvasive biomarkers that predict treatment benefit from biologic therapies in asthma. Ann Am Thorac Soc Suppl:S206–S213. https://doi.org/10.1513/AnnalsATS.201303-047AW

  104. Ko AR, Kim YH, Sol IS, Kim MJ, Yoon SH, Kim KW et al (2016) High-sensitivity C-reactive protein can reflect small airway obstruction in childhood asthma. Yonsei Med J 57:690–697. https://doi.org/10.3349/ymj.2016.57.3.690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Vedel-Krogh S, Rasmussen KL, Nordestgaard BG, Nielsen SF (2020) Complement C3 and allergic asthma: a cohort study of the general population. Eur Respir J. https://doi.org/10.1183/13993003.00645-2020

  106. Rice JL, Diette GB, Suarez-Cuervo C, Brigham EP, Lin SY, Ramanathan M Jr et al (2018) Allergen-specific immunotherapy in the treatment of pediatric asthma: a systematic review. Pediatrics 141:e20173833. https://doi.org/10.1542/peds.2017-3833

    Article  PubMed  Google Scholar 

  107. Miraglia Del Giudice M, Licari A, Brambilla I, Tosca MA, Ciprandi G (2020) Allergen immunotherapy in pediatric asthma: a pragmatic point of view. Children (Basel) 7:58. https://doi.org/10.3390/children7060058

    Article  Google Scholar 

  108. Passalacqua G, Landi M, Peroni DG (2020) Allergen immunotherapy for pediatric asthma: current evidence and knowledge gaps. Curr Opin Allergy Clin Immunol 20(2):162–167. https://doi.org/10.1097/ACI.0000000000000618

    Article  PubMed  Google Scholar 

  109. Tosca MA, Olcese R, Licari A, Ciprandi G (2020) Allergen immunotherapy and asthma. Pediatr Allergy Immunol (Suppl 24):46–48. https://doi.org/10.1111/pai.13161

  110. Larenas-Linnemann D, Wahn U, Kopp M (2014) Use of omalizumab to improve desensitization safety in allergen immunotherapy. J Allergy Clin Immunol 133(3):937,937.e2

    Google Scholar 

  111. Zeidler MR, Kleerup EC, Goldin JG, Kim HJ, Truong DA, Simmons MD et al (2006) Montelukast improves regional air-trapping due to small airways obstruction in asthma. Eur Respir J 27:307–315

    CAS  PubMed  Google Scholar 

  112. Chen X, Wang K, Jiang M, Nong GM (2013) Leukotriene receptor antagonists for small-airway abnormalities in asthmatics: a systematic review and meta-analysis. J Asthma 50:695–704

    CAS  PubMed  Google Scholar 

  113. Barnes PJ (2013) Theophylline. Am J Respir Crit Care Med 88(8):901–906

    Google Scholar 

  114. Currie GP, Srivastava P, Dempsey OJ, Lee DK (2005) Therapeutic modulation of allergic airways disease with leukotriene receptor antagonists. QJM 298:171–182

    Google Scholar 

  115. Rossi A, Pergola C, Koeberle A, Hoffmann M, Dehm F, Bramanti P et al (2010) The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages. Br J Pharmacol 161:555–570

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Brightling CE, Brusselle G, Altman P (2020) The impact of the prostaglandin D2 receptor 2 and its downstream effects on the pathophysiology of asthma. 75(4):761–768

  117. Asano K, Sagara H, Ichinose M, Hirata M, Nakajima A, Ortega H et al (2020) A Phase 2a Study of DP2 Antagonist GB001 for Asthma. J Allergy Clin Immunol Pract 8:1275–1283.e1. https://doi.org/10.1016/j.jaip.2019.11.016

    Article  PubMed  Google Scholar 

  118. Gelb AF, Taylor CF, Simmons M, Shinar C (2009) Role of add-on zileuton on total exhaled, large airway, and small airway/alveolar nitric oxide in moderate-severe persistent adult asthmatics on fluticasone 250 microg/Salmeterol 50 microg. Pulm Pharmacol Ther 22:516–521

    CAS  PubMed  Google Scholar 

  119. Mikailov A, Kane I, Aronoff SC, Luck R, Delvecchio MT (2013) Utility of adjunctive macrolide therapy in treatment of children with asthma: a systematic review and meta-analysis. J Asthma Allergy 6:23–29

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V et al (2013) Azithromycin for prevention of exacerbations in severe asthma 113.(AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 68:322–329

    PubMed  Google Scholar 

  121. Pijnenburg M, Fleming L (2020) Advances in understanding and reducing the burden of severe asthma in children. Lancet Resp Med Available online 7 September 2020. https://doi.org/10.1016/S2213-2600(20)30399-4

  122. Lavorini F, Pedersen S, Usmani OS (2017) Aerosol Drug Management Improvement Team (ADMIT). Dilemmas, confusion, and misconceptions related to small airways directed therapy. Chest. 151:1345–1355

    PubMed  Google Scholar 

  123. van Aalderen WM, Grigg J, Guilbert TW, Roche N, Israel E, Martin RJ et al (2015) Small-particle inhaled corticosteroid as first-line or step-up controller therapy in childhood asthma. J Allergy Clin Immunol Pract 3:721–31.e16. https://doi.org/10.1016/j.jaip.2015.04.012

    Article  PubMed  Google Scholar 

  124. Buhl R, Hamelmann E (2019) Future perspectives of anticholinergics for the treatment of asthma in adults and children. Ther Clin Risk Manag 15:473–485. https://doi.org/10.2147/TCRM.S180890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Murphy KR, Chipps BE (2020) Tiotropium in children and adolescents with asthma. Ann Allergy Asthma Immunol 124:267–276.e3

    PubMed  Google Scholar 

  126. Vogelberg C, Szefler SJ, Vrijlandt EJLE, Boner AL, Engel M, El Azzi G et al (2018) Tiotropium add-on therapy is safe and reduces seasonal worsening in paediatric asthma patients. Eur Respir J 53(6):1801824. https://doi.org/10.1183/13993003.01824-2018

    Article  CAS  Google Scholar 

  127. Hopp R (2019) A perspective on airway hyperresponsiveness in asthma. Eur J Respir Med 1:118–119

    Google Scholar 

  128. Chipps B, Mosnaim G, Mathur SK, Shaikh A, Khoury S, Gopalan G et al (2020) Add-on tiotropium versus step-up inhaled corticosteroid plus long-acting beta-2-agonist in real-world patients with asthma. Allergy Asthma Proc 41:248–255

    CAS  PubMed  Google Scholar 

  129. Abrams EM, Becker AB, Szefler SJ (2018) Current state and future of biologic therapies in the treatment of asthma in children. Pediatr Allergy Immunol Pulmonol 31:119–131

    PubMed  PubMed Central  Google Scholar 

  130. Pasha MA, Jourd'heuil D, Jourd'heuil F, Mahon L, Romero F, Feustel PJ et al (2014) The effect of omalizumab on small airway inflammation as measured by exhaled nitric oxide in moderate-to-severe asthmatic patients. Allergy Asthma Proc 35:241–249

    CAS  PubMed  Google Scholar 

  131. Paganin F, Mangiapan G, Proust A, Prudhomme A, Attia J, Marchand-Adam S et al (2017) Lung function parameters in omalizumab responder patients: an interesting tool? Allergy. 72:1953–1961

    CAS  PubMed  Google Scholar 

  132. Hanania NA, Djukanovic R, Heaney LG, Yang M, Yoo B, Iqbal A et al (2020) Determinants of lung function improvement with omalizumab in adults with allergic asthma. J Allergy Clin Immunol Pract 8:2068–2070

    PubMed  Google Scholar 

  133. Sposato B, Camiciottoli G, Bacci E, Scalese M, Carpagnano GE, Pelaia C et al (2020) Mepolizumab effectiveness on small airway obstruction, corticosteroid sparing and maintenance therapy step-down in real life. Pulm Pharmacol Ther 61:101899

    CAS  PubMed  Google Scholar 

  134. Agache I, Akdis C, Akdis M, Canonica GW, Casale T et al (2020) EAACI biologicals guidelines—recommendations for severe asthma. Allergy. https://doi.org/10.1111/all.14425

  135. Brand PL, Makela MJ, Szefler SJ, Frischer T, Price D (2015) ERS Task Force Monitoring Asthma in Children. Monitoring asthma in childhood: symptoms, exacerbations and quality of life. Eur Respir Rev 24:187–193. https://doi.org/10.1183/16000617.00003614

    Article  PubMed  Google Scholar 

  136. Pijnenburg MW, Baraldi E, Brand PL, Carlsen KH, Eber E, Frischer T et al (2015) Monitoring asthma in children. Eur Respir J 45:906–925

    PubMed  Google Scholar 

  137. Wildfire JJ, Gergen PJ, Sorkness CA, Mitchell HE, Calatroni A, Kattan M et al (2012) Development and validation of the composite asthma severity index--an outcome measure for use in children and adolescents. J Allergy Clin Immunol 129:694–701

    PubMed  PubMed Central  Google Scholar 

  138. Zeiger RS, Szefler SJ, Phillips BR, Schatz M, Martinez FD, Chinchilli VM et al (2006) Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma. J Allergy Clin Immunol 117:45–52

    CAS  PubMed  Google Scholar 

  139. Larsen GL, Morgan W, Heldt GP, Mauger DT, Boehmer SJ, Chinchilli VM et al (2009) Impulse oscillometry versus spirometry in a long-term study of controller therapy for pediatric asthma. J Allergy Clin Immunol 12:861–7.e1. https://doi.org/10.1016/j.jaci.2008.10.036

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of Nebraska Medical Center and Children’s Hospital and Medical Center, Omaha, NE, 68114, USA

    Russell J. Hopp & Mark C. Wilson

  2. Division of Allergy and Immunology, Albany Medical College, 176 Washington Avenue Extension, Suite 102, Albany, NY, 12203, USA

    M. Asghar Pasha

Authors
  1. Russell J. Hopp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark C. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Asghar Pasha
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Each author provided significant contribution.

Corresponding author

Correspondence to Russell J. Hopp.

Ethics declarations

Conflict of Interest

N/A

Ethics Approval

N/A

Consent to Participate

N/A

Consent for Publication

N/A

Code Availability

N/A

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hopp, R.J., Wilson, M.C. & Pasha, M.A. Small Airway Disease in Pediatric Asthma: the Who, What, When, Where, Why, and How to Remediate. A Review and Commentary. Clinic Rev Allerg Immunol 62, 145–159 (2022). https://doi.org/10.1007/s12016-020-08818-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-020-08818-1

Keywords

Search

Navigation