The presence of neutrophils, the cytokines IL-10, and IFN-γ and, more particularly, TNF-α, and GM-CSF in the sputum may play an important role in the pathophysiological mechanism of STRA in children and adolescents. Specific antagonists for these cytokines may represent a future therapeutic strategy.

Aos meus amados pais Vagner I. Vergani e Ana Maria P. Vergani.Ao meu querido esposo Rodrigo P. Cuano.À minha família, meu alicerce. AGRADECIMENTOSA Deus referencial absoluto em minha vida, sem Sua presença esta pesquisa seria inviável, pois Dele é proveniente todo o Conhecimento.Ao querido amigo e Prof. Dr. Joaquim Carlos Rodrigues pela orientação inegavelmente competente e segura, pelos valiosos estímulos e sugestões concedidas, a ele minha admiração.Ao Rodrigo, meu marido, pela sua paciência, compreensão, amor, incentivo, ajuda e capacidade intelectual que muito contribuíram neste percurso.

Background Studies in adult severe treatment-resistant asthma (STRA) have demonstrated heterogeneous pathophysiology. Studies in the pediatric age group are still scarce, and few include bronchial tissue analysis. Objective We investigated 6–18-year-old patients diagnosed with STRA in Sao Paulo, Brazil, by characterizing the different lung compartments and their correlations with asthma control and lung function. Methods Inflammatory profiles of 13 patients with a confirmed diagnosis of STRA were analyzed using blood, induced sputum, bronchoalveolar lavage, viral and bacterial screens and endobronchial biopsy. Inflammatory cells, cytokines, and basement membrane thickening were tested for correlations with the asthma control test (ACT) and spirometry and plethysmography parameters. Results Endobronchial biopsy specimens from 11 patients were viable for analysis. All biopsies showed eosinophilic infiltration. Submucosal (SM) eosinophils and neutrophils were correlated with worse lung function (pre-BD FEV1), and SM neutrophils were correlated with fixed obstruction (post-BD FEV1). Intraepithelial (IE) neutrophils were positively correlated with lung function (pre-BD sGaw). CD8 + T cells had the highest density in the IE and SM layers and were positively correlated with ACT and negatively correlated with the cytokines IL1β, IL2, IL5, IL7, IL10, IL12, IL17, GCSF, MCP-1, INF-δ, and TNFα in sputum supernatant. The ASM chymase + mast cell density correlated positively with quality-of-life score (pAQLQ) and ACT. Conclusion Eosinophils and SM neutrophils correlated with worse lung function, while IE neutrophils correlated with better lung function. Most importantly, CD8 + T cells were abundant in bronchial biopsies of STRA patients and showed protective associations, as did chymase + mast cells.

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