Lung inflammation and simulated airway resistance in infants with cystic fibrosis

https://doi.org/10.1016/j.resp.2021.103722Get rights and content

Highlights

  • We used computational fluid dynamics (CFD) to evaluate lung structure and function from chest CT scans from 18 infants with CF.

  • Airway resistance was increased in infants with CF. Airway resistance was simulated in both full airway models with an average of 51 bronchi and in models trimmed to 33 bronchi.

  • Simulated airway resistance was associated with inflammation in bronchoalveolar lavage fluid obtained 8 months earlier, including percent neutrophils and interleukin-8.

Abstract

Cystic fibrosis (CF) is characterized by small airway disease; but central airways may also be affected. We hypothesized that airway resistance estimated from computational fluid dynamic (CFD) methodology in infants with CF was higher than controls and that early airway inflammation in infants with CF is associated with airway resistance. Central airway models with a median of 51 bronchial outlets per model (interquartile range 46,56) were created from chest computed tomography scans of 18 infants with CF and 7 controls. Steady state airflow into the trachea was simulated to estimate central airway resistance in each model. Airway resistance was increased in the full airway models of infants with CF versus controls and in models trimmed to 33 bronchi. Airway resistance was associated with markers of inflammation in bronchoalveolar lavage fluid obtained approximately 8 months earlier but not with markers obtained at the same time. In conclusion, airway resistance estimated by CFD modeling is increased in infants with CF compared to controls and may be related to early airway inflammation.

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.

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