BACKGROUND
 
The human airways consist of approximately 23 generations of dichotomously branching tubes from the trachea to the alveoli. From generation 8 downstream, the small airways (< 2 mm in diameter) lack cartilaginous support, being more easily compressible/collapsible. Given the exponential increase in airway numbers, there is a rapid increase in total cross-sectional area; thus, airflow velocity decreases, and small airways resistance comprises only 10-20% of total airways resistance. It follows that extensive functional abnormalities in the so-called “silent zone” might not be detected by routine pulmonary function tests.(1)
 
OVERVIEW
 
A 68-year-old nonsmoker male (BMI = 41.2 kg/m2) was referred for respiratory assessment due to insidious exertional dyspnea and dry cough. He had undergone hematopoietic stem cell transplantation approximately one year prior in the setting of acute myeloblastic leukemia. There was no clinical or laboratory evidence of graft-versus-host disease. Spirometry revealed no obstruction, and FEF25-75% was reduced in proportion to a low FVC. Plethysmography showed a trend toward low “static” lung volumes and high specific airway resistance. Taken together, these results were considered equivocal in a severely obese subject(2) with a history of right upper lobectomy for congenital disease. Given concerns of incipient bronchiolitis obliterans, he was referred for more sensitive tests of small airway disease (SAD), the results of which were as follows: increased phase III slope and closing capacity (single-breath N2 washout), increased ventilation heterogeneity in acinar airways relative to conducting airways (multiple-breath N2 washout), and increased difference between resistance at 5 Hz and 20 Hz (impulse oscillometry). As it can be seen in Chart 1, these results were indeed consistent with SAD. Despite mild gas trapping without mosaic attenuation on chest CT, the consistency of the functional findings prompted immunosuppressive therapy. At the three-month follow-up visit, there was resolution of symptoms and uniform improvement in all functional markers of SAD.

 

 
Diagnosing SAD might be clinically relevant in the initial stages of several obstructive lung diseases, including asthma,(3) cystic fibrosis, and COPD. Tests of SAD may also reveal unsuspected airway abnormalities in sarcoidosis and some interstitial lung diseases, such as hypersensitivity pneumonitis and nonspecific interstitial pneumonia. Detecting SAD may change management in connective tissue diseases (e.g., rheumatoid arthritis, mixed disease), inflammatory bowel diseases, bone marrow and lung transplantation, common variable immunodeficiency disorders, diffuse panbronchiolitis, and diseases related to environmental exposures to pollutants, allergens, and drugs.(4) As herein described, insidious SAD might be a late complication of hematopoietic stem cell transplantation, even in the absence of graft-versus-host disease. Prompt aggressive treatment is paramount to improving survival.(5)
 
CLINICAL MESSAGE
 
Although physiological tests interrogating the “silent zone” are not widely available, they can provide valuable information in cases when the diagnosis and quantification of SAD might impact on clinical decision making. The lack of reliable reference values and cut-offs for abnormality remains an extant issue: in many circumstances, longitudinal worsening—or improvement in response to treatment—is more useful. If feasible, combining techniques (Chart 1) further improves diagnostic accuracy.
 
REFERENCES
 
1.            Woolcock AJ, Vincent NJ, Macklem PT. Frequency dependence of compliance as a test for obstruction in the small airways. J Clin Invest. 1969;48(6):1097-1106. https://doi.org/10.1172/JCI106066
2.            Neder JA, Berton DC, O’Donnell DE. Obesity: how pulmonary function tests may let us down. J Bras Pneumol. 2020;46(3):e20200116. https://doi.org/10.36416/1806-3756/e20200116
3.            Jackson N, Rafique J, Singh D. Identifying small airway dysfunction in asthma in clinical practice. J Bras Pneumol. 2020;46(2):e20200046. https://doi.org/10.36416/1806-3756/e20200046
4.            Burgel PR, Bergeron A, de Blic J, Bonniaud P, Bourdin A, Chanez P, et al. Small airways diseases, excluding asthma and COPD: an overview. Eur Respir Rev. 2013;22(128):131-147. https://doi.org/10.1183/09059180.00001313
5.            Busmail A, Penumetcha SS, Ahluwalia S, Irfan R, Khan SA, Rohit Reddy S, et al. A Systematic Review on Pulmonary Complications Secondary to Hematopoietic Stem Cell Transplantation. Cureus. 2022;14(5):e24807. https://doi.org/10.7759/cureus.24807