Lung inflammation and simulated airway resistance in infants with cystic fibrosis
Introduction
Cystic fibrosis (CF) is an autosomal recessive genetic disease marked by abnormal mucus production, chronic airway inflammation and infection leading to structural airway injury and bronchiectasis (O’Sullivan and Freedman, 2009; Sanders et al., 2014). Human and animal studies have demonstrated that the CF airway is abnormal from birth, with airway shape abnormalities, including reduced caliber and less circular shape, seen in the CF human infant and CF pig at birth (Meyerholz et al., 2018, 2010; Ranganathan et al., 2017). Despite these congenital abnormalities, airway disease in infants with CF is often clinically “silent” without overt respiratory symptoms. Cohort studies have been conducted during infancy and young childhood to identify this subtle, early airway disease (Ranganathan et al., 2017; Simpson et al., 2013; Sly et al., 2013). To better understand this airway disease, evaluations beyond history and physical examination are performed, including chest computed tomography (CT) scans, multiple breath washout, infant pulmonary function tests, and bronchoscopy with bronchoalveolar lavage fluid (BALF) collection (Ramsey et al., 2016). Imaging studies have confirmed abnormal airway findings including abnormal tracheal cartilage, tracheomalacia, and bronchiectasis (Fischer et al., 2014; Meyerholz et al., 2010; Rosenow et al., 2015).
Chest CT images are the gold standard to define airway structure. Computational fluid dynamic (CFD) modeling methods can be used to estimate functional abnormalities from volumetric chest CT images. The primary results of CFD modeling are estimated airway pressures, airway resistance, and airflow patterns. CFD techniques have been used to reveal increased airway resistance in infants with left pulmonary artery sling (Qi et al., 2014) and in infants with tracheomalacia (Gunatilaka et al., 2020), and decreases in resistance have been noted after airway stenting (Ho et al., 2012). Based on CFD model simulations of the CF pig airway, the tracheal shape differences seen at birth result in both increased airway resistance and airflow velocity (Awadalla et al., 2014). CFD models have also predicted alterations in drug particle deposition in the pig model and older patients with CF (Bos et al., 2015). CFD has not been described in infants with CF during the clinically silent period.
We hypothesized that airway resistance, estimated using CFD models created from chest CT scans, would be higher in infants with CF than controls. We explored CFD models using all visualized airways and a model that isolated more central airways by trimming the most distal airways. A secondary aim was to evaluate the association of early airway inflammation with airway resistance in infants with CF.
Section snippets
Study subjects
This project utilized volumetric chest CT images and physiologic results from 20 infants who participated in an international prospective observational study entitled the Viral Pathogenesis of Early Cystic Fibrosis Lung disease (NCT01973192)(Deschamp et al., 2019). Data from two study sites: 1) Royal Children’s Hospital in Melbourne, AUS and 2) Riley Children’s Hospital in Indianapolis, Indiana, USA are presented in this manuscript. CT scans from two children with CF had poor image quality and
Results
18 infants with CF (11 females) and 7 control patients (1 female) were included. There was a difference in the number of females in the CF group versus the control group (p = 0.07). Median age at chest CT scan for infants with CF was 13 months (IQR: 12.9–15.2 months) compared to 15 months (IQR: 13.0–15.9) for controls. Other relevant characteristics were not different between the CF and control groups (Table 1, supplementary Table 1). The cohort of infants with CF from the USA were older than
Discussion
CFD methodology translates airway anatomy into an estimate of pulmonary function, in this case airway resistance. If the airways are narrower, longer, or more tortuous, the resistance will increase. The models created from infants with CF do not appear visually abnormal (Fig. 3), but we found that estimates of airway resistance were higher in the infants with CF compared to controls. Tracheal resistance did not appear significantly different between the groups, indicating that the
Author contributions
Emily M DeBoer: Investigation, Writing Original draft, Review, and Editing
Julia S Kimbell: Conceptualization, Methodology, Validation, Investigation
Kaci Pickett: Formal analysis, Writing – Review and Editing
Joseph E Hatch: Investigation, resources, project administration, Writing Review and Editing
Kathryn Akers: Resources, Investigation
John Brinton: Formal analysis
Graham L Hall: Conceptualization, Editing
Louise King: Resources, project administration
Fiona Ramanauskas: Investigation
Tim Rosenow:
Funding
Supported by NHLBI Viral Pathogenesis of Early CF Lung Disease study (R01HL116211) PI Davis, Ferkol, Ranganathan, DeBoer 18A0 Cystic Fibrosis Foundation, and AREST CF NHMRC1043768 PI Ranganathan, and NIH/NCATS Colorado CTSI UL1 TR002535. Contents are the authors’ sole responsibility and do not necessarily represent official NIH views.
Declaration of Competing Interest
Dr. DeBoer reports grants from Cystic Fibrosis Foundation, grants from NIH/NCATS Colorado CTSI, during the conduct of the study; personal fees from Boehringer Ingelheim, personal fees from Triple Endoscopy, outside the submitted work. In addition, Dr. DeBoer has a patent Endoscopic methods and technologies pending. Dr. Kimbell reports grants from Indiana University, during the conduct of the study; grants from Applied Research Associates, Inc., grants from Kitware, Inc., outside the submitted
Acknowledgements
The authors thank Nadeene Clarke, Royal Children’s Hospital Melbourne, for her quick response to questions. The authors thank Dr. Rob Tepper for his stimulating conversation about airways. Dr. DeBoer thanks Drs. Scott Sagel, Robin Deterding, Bradford Smith, and Deb Liptzin for their support and mentorship in this project.
References (38)
- et al.
Automated CT scan scores of bronchiectasis and air trapping in cystic fibrosis
Chest
(2014) - et al.
Early respiratory viral infections in infants with cystic fibrosis
J. Cyst. Fibros.
(2019) - et al.
A hierarchical stepwise approach to evaluate nasal patency after virtual surgery for nasal airway obstruction
Clin, Biomech, (Bristol, Avon)
(2019) - et al.
Changes in nasal airflow and heat transfer correlate with symptom improvement after surgery for nasal obstruction
J. Biomech.
(2013) - et al.
Lack of cystic fibrosis transmembrane conductance regulator disrupts fetal airway development in pigs
Lab. Invest.
(2018) - et al.
Assessment of early bronchiectasis in young children with cystic fibrosis is dependent on lung volume
Chest
(2013) - et al.
Cystic fibrosis
Lancet
(2009) - et al.
Early detection of lung disease in children with cystic fibrosis using lung function
Paediatr. Respir. Rev.
(2008) - et al.
Early airway structural changes in cystic fibrosis pigs as a determinant of particle distribution and deposition
Ann. Biomed. Eng.
(2014) - et al.
Critical Reynolds number for a natural transition to turbulence in pipe flows
Phys. Rev. Lett.
(2007)
Patient-specific modeling of regional antibiotic concentration levels in airways of patients with cystic fibrosis: are we dosing high enough?
PLoS One
Correlation of forced oscillation technique in preschool children with cystic fibrosis with pulmonary inflammation
Thorax
Lung function from infancy to preschool in a cohort of children with cystic fibrosis
Eur. Respir. J.
Computed tomography reflects lower airway inflammation and tracks changes in early cystic fibrosis
Am. J. Respir. Crit. Care Med.
Multicenter evaluation of infant lung function tests as cystic fibrosis clinical trial endpoints
Am. J. Respir. Crit. Care Med.
Tracheomalacia is associated with lower FEV1 and Pseudomonas acquisition in children with CF
Pediatr. Pulmonol.
Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis
Eur. Respir. J.
Increased Work of Breathing due to Tracheomalacia in Neonates
Ann. Am. Thorac. Soc.
Numerical analysis of airflow alteration in central airways following tracheobronchial stent placement
Exp. Hematol. Oncol.
Cited by (5)
Effects of elexacaftor-tezacaftor-ivacaftor on daily treatment burden and airflow obstruction in adults with cystic fibrosis
2023, Pulmonary Pharmacology and TherapeuticsExperimental analysis and biaxial biomechanical behaviour of ex-vivo sheep trachea
2023, Frontiers in MaterialsComputational, Ex Vivo, and Tissue Engineering Techniques for Modeling Large Airways
2023, Advances in Experimental Medicine and BiologyThe P2X7 Receptor in Cystic Fibrosis Monocytes Linking CFTR Deficiency to Inflammation
2022, American Journal of Respiratory and Critical Care Medicine