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Inflammation in Large and Small Airways

Asthmatic inflammation has been shown to occur along the entire length of the airway, throughout the tracheobronchial tree — from the large central airways all the way down to the small distal airways.

The total surface area of the small distal airways is much greater than that of the large central airways, so inflammation along these distal surfaces may make a significant contribution to the symptoms of asthma.

Acute and chronic inflammation can increase bronchial hyperresponsiveness and enhance susceptibility to bronchospasm. Allergens such as pollen, cat dander, and mold spores have particle sizes small enough to reach the smallest airways, where they can trigger asthma symptoms if the airways are inflamed.

References:

  1. Hamid Q. Pathogenesis of Small Airways in Asthma. Respiration. 2012;84:4–11.
  2. Leach C, Colice GL, Luskin A. Particle size of inhaled corticosteroids: Does it matter? J Allergy Clin Immunol. 2009;124:S88-S93.
  3. National Asthma Education and Prevention Program (NAEPP). Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma–Full Report 2007. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health, Lung, and Blood Institute; August 2007. https://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-report. Accessed October 14, 2017.
  4. van der Wiel E, ten Hacken NHT, Postma DS, van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: A systematic review. J Allergy Clin Immunol. 2013;131:646-657.

Importance of Treating Small Airways

Treatment with anti-inflammatory drugs can usually reverse some of the airway inflammation and hyperresponsiveness.

Since inflammation, remodeling, and obstruction can occur in airways of all sizes, it is important for the anti-inflammatory treatment to be able to reach all the airways.

Delivering Anti-inflammatory Medication to Distal Airways

  • Anti-inflammatory treatment needs to be directed to both the large and small airways in order to reach all the areas that might have inflammation.
  • One study showed that Iarge inhaled corticosteroid (ICS) particles (2.6–4.5 μm diameter) had <20% deposition in the lung, whereas small ICS particles (<2 μm) had >50% lung deposition.
  • Small ICS particles (<2 μm) are more likely to reach the small airways (defined as <2 μm in diameter) where they can exert their anti-inflammatory effect.

Steroid Receptors

  • Steroid receptors are present in nearly all cells of the respiratory tract, and the smaller airways actually have even more steroid receptors than the large airways.
  • It has been shown that ICSs have a topical anti-inflammatory effect at the location where they are deposited in the lung tissue – not through systemic absorption.
  • Increasing the precision of ICS delivery and deposition has the potential to enhance the anti-inflammatory effects.

Asthma Control

Inflammation and remodeling in small airways has been shown to contribute to clinical asthma symptoms.

Specifically, greater dysfunction of the small airways – but not the large airways – has been associated with worse asthma control.

It is harder to keep asthma under control if the medicine cannot reach the small airways.

Multiple clinical studies, including rigorous dose-response studies and comparative clinical trials against CFC inhalers have shown that when small-particle ICS drug delivery enables more deposition throughout the lung, there is an improvement in clinical efficacy and comparable asthma control at lower doses.

Treatment directed toward reducing inflammation can reduce airway hyperresponsiveness and improve asthma control.

References:

  1. Hamid Q. Pathogenesis of Small Airways in Asthma. Respiration. 2012;84:4–11.
  2. Leach C, Colice GL, Luskin A. Particle size of inhaled corticosteroids: Does it matter? J Allergy Clin Immunol. 2009;124:S88-S93.
  3. Martin RJ. Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin Immunol. 2002;109 (Suppl 2):S447-S460.
  4. National Asthma Education and Prevention Program (NAEPP). Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma–Full Report 2007. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health, Lung, and Blood Institute; August 2007. https://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-report. Accessed October 14, 2017.
  5. van der Wiel E, ten Hacken NHT, Postma DS, van den Berge M. Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: A systematic review. J Allergy Clin Immunol. 2013;131:646-657.

National Guidelines for Using ICS in Asthma Treatment

See below for important information about national asthma treatment guidelines.

The National Asthma Education and Prevention Program (NAEPP) and the Food and Drug Administration (FDA) recommend inhaled corticosteroids (ICS) as an essential part of treatment for patients with persistent asthma

NAEPP guidelines for management of mild persistent asthma in adolescents ≥12 and adults:

  • Initiate long-term control therapy with an inhaled corticosteroid (ICS) at a low dose
  • If that is insufficient for asthma control, the next step would be either adding a long-acting beta-agonist (LABA) to low-dose ICS or increasing the ICS dose to the medium dose range

FDA recommendations:

  • ICS and long-acting beta-agonist (LABA) combinations should only be prescribed if necessary for patients whose asthma is not adequately controlled on long-term ICS monotherapy
  • Once asthma control is achieved and maintained, assess patients regularly and initiate step-down therapy (e.g., discontinue LABA) if possible without loss of asthma control, and continue to treat the patient with a long-term asthma control medication, such as an ICS
  • Adolescent patients who require the addition of a LABA to ICS therapy should use a combination product containing both an ICS and a LABA to ensure adherence with both medications

References:

  1. National Asthma Education and Prevention Program (NAEPP). Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma–Full Report 2007. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health, Lung, and Blood Institute; August 2007. https://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/full-report. Accessed October 14, 2017.
  2. US Food and Drug Administration. FDA Drug Safety Communication: Drug labels now contain updated recommendations on the appropriate use of long-acting inhaled asthma medications called Long-Acting Beta-Agonists (LABAs). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213836.htm. Updated June 2, 2010. Accessed October 15, 2017.