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Histopathology of severe childhood asthma: a case series
Henry A Jenkins1, Carlyne Cool, Stanley J Szefler
1Ira J. and Jacqueline Neimark Laboratory of Clinical Pharmacology in Pediatrics, Division of Clinical Pharmacology, National Jewish Medical and Research Center, Denver, CO, USA.
Insights
Severe childhood asthma may not always involve significant airway inflammation, challenging current treatment models. Airway remodeling can occur without inflammation, and lung function can improve despite these changes, suggesting new therapeutic targets.
Area of Science:
- Pediatric Pulmonology
- Respiratory Pathology
- Asthma Research
Background:
- The current understanding of severe asthma pathology emphasizes persistent airway inflammation leading to symptoms, hyperresponsiveness, and irreversible lung function loss.
- Limited research exists on the specific pathology of severe childhood asthma.
Observation:
- This study evaluated six children with difficult-to-control asthma who underwent bronchoscopy and endobronchial biopsy.
- Biopsies revealed airway remodeling, including basement membrane thickening and smooth muscle hypertrophy, in all patients.
- Notably, five of six patients showed minimal evidence of airway inflammation.
Findings:
- Airway remodeling, characterized by subbasement membrane thickening, was present in all cases but did not correlate with lung function parameters.
- Despite significant remodeling, the majority of patients achieved normal forced expiratory volume in 1 second (FEV1) values.
- Histological examination revealed minimal to no airway inflammation, with an absence of eosinophils and neutrophils.
Implications:
- These findings challenge the central role of inflammation in severe asthma pathology and suggest limitations of the current inflammatory paradigm.
- The presence of significant airway remodeling without substantial inflammation indicates a need to explore alternative therapeutic targets beyond anti-inflammatory agents.
- Further research is warranted to understand the mechanisms driving lung function lability and remodeling in severe asthma and to develop more effective treatment strategies.
Background:
To date, little has been published describing the pathology of severe childhood asthma. The currently accepted model of asthma holds that persistent airway inflammation leads to various symptoms of asthma, airway hyperresponsiveness, and airway remodeling that ultimately results in permanent loss of lung function.
Methods:
Evaluation of six children referred to the National Jewish Medical and Research Center with difficult-to-control asthma, despite aggressive anti-inflammatory therapy, who underwent bronchoscopy with endobronchial biopsy to better characterize their disease.
Results:
In every case, endobronchial biopsies revealed changes consistent with airway remodeling characterized by thickening of the basement membrane, smooth-muscle hypertrophy, with varying degrees of goblet-cell and submucous gland hyperplasia. The degree of subbasement membrane thickening did not appear to correlate with baseline FEV(1), ultimate FEV(1) following aggressive therapy, or lability in lung function. In five of six cases, there was minimal to no histologic evidence for airway inflammation with mild and patchy submucosal lymphocytic infiltration noted; eosinophils and neutrophils were not present. Further, the majority of the patients achieved normal FEV(1) values despite significant subbasement membrane thickening, counter to the current beliefs regarding airway remodeling and irreversible loss of lung function.
Conclusions:
This case report highlights some of the shortcomings of the current inflammatory paradigm for severe asthma. Despite little evidence of ongoing airway inflammation, many of the subjects displayed significant lung function lability. The lack of inflammation argues against steroid resistance at a cellular level, although it could be argued that inflammation may have been distal to the site sampled. Additionally, normal to nearly normal lung function was achieved despite the presence of significant remodeling. These findings suggest the need to look beyond inflammation to fully treat severe asthma and ultimately alter its progression.