Future exacerbations in children with severe wheeze predicted by bronchial remodeling
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Key takeaways:
- Using bronchial remodeling phenotypes, children who wheeze with a possibility for future exacerbations were found.
- Several parameters of remodeling made up those who faced higher risks after bronchoscopy.
The risk for regular and severe future exacerbations in children aged 1 to 5 years with severe wheeze can be found through bronchial remodeling, according to results published in American Journal of Respiratory and Critical Care Medicine.
“Preschool wheezers represent a heterogeneous population,” Michael Fayon, MD, PhD, physician and clinical researcher in the Pediatric Pulmonology Unit at Bordeaux University Hospital, and colleagues wrote. “Beyond the visible clinical symptoms and/or functional impairment, bronchial remodeling may occur early and impact long-term outcomes. Previous studies have identified several phenotypes of preschool wheezers using either cluster analysis or latent class analysis by inputting clinical, functional, and/or biological data. However, there is a lack of data regarding latent class analysis on the basis of bronchial remodeling parameters as a method to categorize preschool wheezers.”
In a double-center prospective study, Fayon and colleagues evaluated 56 patients aged 1 to 5 years diagnosed as severe wheezers who needed fiberoptic bronchoscopy to determine bronchial-remodeling-based latest classes of these patients and then assess them against each other to look at differences in outcomes after bronchoscopy.
In a latent class analysis, researchers included various bronchial remodeling parameters from the children’s bronchial biopsies such as epithelial integrity, reticular basement membrane (RBM) thickness, mucus gland, fibrosis and bronchial smooth muscle (BSM) areas, the density of blood vessels and RBM-BSM distance in order to categorize and identify patients who may be at risk for exacerbations.
Notably, every child was receiving high-dose inhaled corticosteroids, according to researchers.
Bronchial remodeling classes, risks
Of the total cohort, researchers found that the procedure was well tolerated, with only 17 children experiencing an adverse event. For all but two of these children, the event went away within 72 hours.
Due to problems with biopsies, the final analysis included 52 children.
Latent class analysis separated these children into either Class BR1 (n = 38) or Class BR2 (n = 14). When comparing the children from the two classes, researchers found that those in BR1 had higher density of blood vessels, RBM thickness and normalized BSM area, as well as lower mucus gland area, RBM-BSM distance and fibrosis area. Epithelial integrity was comparable in both classes.
One year prior to the bronchoscopy procedure, clinical and functional characteristics of both classes were similar, according to researchers.
However, in the year following the procedure, researchers found some differences between the two groups, with class BR1 showing less time to first exacerbation (HR = 2.041; 95% CI, 1.01-4.13), a higher average number of exacerbations per patient (3 vs. 1; P = .004) and more patients experiencing three or more exacerbations a year (22 patients vs. 0 patients; P < .001). With these findings, a 39.6 (95% CI, 2.2-712; P < .0001) higher odds for having an exacerbation was observed in those who fit in class BR1 than those in class BR2.
Compared with class BR2, researchers further found that 12 months after the procedure, patients in class BR1 had more emergency visits (0 vs. 1; P = .022) and a greater number of hospitalized patients (0 patients vs. 17 patients; P = .002).
Validation cohort, other parameters
Researchers validated their findings through a separate cohort of 44 children aged 1 to 5 years with severe wheezing; however, full bronchial remodeling data was only found for 28 of these children (class BR1 = 19 patients; class BR2 = 9 patients). In this analysis, Fayon and colleagues found comparable results to their main analysis with class BR1 again having shorter time to first exacerbation (HR = 2.83; 95% CI, 1.02-7.8), a greater average number of exacerbations per patient (3 vs. 0; P = .004) and more patients experiencing three or more exacerbations (11 patients vs. 0 patients; P = .004).
Lastly, thinking about the scenario where there is no data on bronchial remodeling parameters, researchers combined both cohorts (n = 100) to see if clinical and biological parameters-based latest classes could be used to find those with a risk for future exacerbations.
Between those in class CB1 (n = 75) and CB2 (n = 25) in this analysis, several parameters at baseline and outcomes during the year following the procedure did not differ significantly: BAL cytology, BAL microbiology, bronchial remodeling parameters, time to first exacerbation, total number of exacerbations per patient, average number of exacerbations per patient and number of patients with three or more exacerbations. This indicates that these parameters cannot find patients who face a higher risk for exacerbations in the future, according to researchers.
“Because the present study was not interventional on the one hand, and, on the other hand, the complete assessment of bronchial remodeling required invasive biopsies with a dedicated immunohistochemical setup, it remains difficult to conclude that our findings are helpful for clinicians to better characterize severe preschool wheezers and to identify patients at risk of frequent exacerbations,” Fayon and colleagues wrote. “Thus, the next steps should be: 1) to confirm our results through further longitudinal studies; 2) to find less invasive biomarkers of bronchial remodeling that could be applied in the clinic; and 3) to understand the mechanisms that underpin the different types of remodeling in the two classes, to be able to target interventions.”
This study by Fayon and colleagues adds to literature on the relationship between wheeze phenotypes, airway remodeling and outcomes; however, there are several limitations to keep in mind when assessing these results, including the lack of data on lung function, according to an accompanying editorial by Sejal Saglani, MD, professor of pediatric respiratory medicine in the National Heart & Lung Institute at Imperial College London, and Simonetta Baraldo, PhD, professor in the department of cardiac, thoracic, vascular sciences and public health at the University of Padova and Padova City Hospital in Italy.
“There were no assessments of lung function at follow-up to help understand whether any features might specifically be associated with poor lung function outcomes,” Saglani and Baraldo wrote. “Knowing the high likelihood of the children who were included in this study being set on a low lung function trajectory, it would have been helpful to know whether lung function declined over the year of follow-up and whether the remodeling phenotype associated with exacerbations was associated with worse lung function.”
Saglani and Baraldo conclude that these findings spark the importance of continuing to study remodeling in the context of wheezing.
“The need for interventions that impact multiple remodeling features is apparent,” they wrote. “In addition, the huge challenge of finding noninvasive biomarkers that may reflect remodeling has still to be overcome. But the data from Fayon and colleagues now highlight the role of early structural airway changes in determining short-term adverse outcomes in addition to their importance in influencing long-term outcomes. This study suggests a complete re-think in our approach to the management of recurrent severe, troublesome wheezing is urgently needed, with therapeutic interventions that can target remodeling remaining a critical unmet need.”