How Can Measuring Distal Airway Inflammation Help Predict Asthma Exacerbations?

Patient, Human Face, Brazil, Asthmatic, Child
Researchers investigated whether measuring distal airway inflammation with variable flow measurements of FeNO could serve as an improved marker for asthma risk in children.

Alveolar concentration of nitric oxide (CalvNO), a marker of distal airway inflammation, greater than 7 ppb is highly specific for an asthma attack and improves prediction of an attack in children in the next 4 months, according to findings published in the European Respiratory Journal.

The current correlation is poor between physiological parameters and distal inflammation measured directly. Transbronchial biopsy is invasive and unsuitable for routine monitoring. Researchers sought to determine if measurement of CalvNO using variable flow measurements of fractional exhaled nitric oxide (FeNO) would be a more effective assessor of future risk for asthma exacerbation than current markers of exhaled nitric oxide at an expiratory flow rate of 50 ml/sec (FeNO50) and bronchial nitric oxide flux, (JawNO), both of which measure more proximal inflammation.

For the prospective study, researchers enrolled 68 children aged greater than 6 years (mean age 9.0±2.4 years, 45 boys) from the asthma outpatient clinic of the Paediatric Respiratory Unit of the University Hospital of Alexandroupolis, Greece. All study participants had been diagnosed with asthma, had allergic rhinitis, and had been sensitized to aeroallergens.

All patients also had a history of at least 2 symptoms, including: chest tightness, recurrent wheeze, shortness of breath, cough. All participants showed a 15% increase in first second forced expired volume (FEV1) after administration of 400 mcg short-acting β-2 agonist and exclusion of other diseases mimicking asthma. After enrollment, then at a second visit 4 months later, then a third visit 4 months after the second visit, measurements were recorded for the Childhood Asthma Control Test, spirometry pre- and post-bronchodilator administration, FeNO50, JawNO, CalvNO. Moderate (deterioration in lung function, deterioration in symptoms, increased rescue bronchodilator use lasting at least 2 days but not severe enough for systemic corticosteroids or hospitalization) or severe (requiring high dose oral corticosteroids for at least 3 days, increase in maintenance oral corticosteroid dose, emergency department visit or hospitalization) exacerbations were noted.

Increased risk of asthma exacerbation in the following 4 months was associated with CalvNO and no other inflammation parameter. Decreased forced mid-flows in children with CalvNO greater than 7 ppb suggests that CalvNO is a marker of small airway disfunction in asthma. That level of CalvNO is highly specific but not sensitive for a subsequent exacerbation, and a level less than 4 ppb excluded risk of attack also with high specificity and low sensitivity.

Researchers noted study limitations that some significant risk factors for asthma exacerbation were not included; they made no attempt to see if small particle inhaled corticosteroid reduced exacerbation risk in those with high CalvNO; they had no data on lung diffusion capacity and could not assess other meaningful factors; and their results have not been repeated.

“The risk of an asthma exacerbation associated with small airway inflammation, as measured by CalvNO, underscores the importance of distal as well as proximal airways disease in the pathophysiology of asthma,” the study authors wrote.

They concluded, “whether partitioning nitric oxide has clinical value depends on whether taking action on the results improves outcomes.”


Paraskakis E, Sarikloglou E, Fouzas S, Steiropoulos P, Tsalkidis A, Bush A. Improved prediction of asthma exacerbations by measuring distal airway inflammation. Eur Respir J. Published online January 27, 2022. doi:10.1183/13993003.01684-2021