Background: Recent studies increasingly suggest that airway microbiome plays a critical role in respiratory health and disease, including the potential influence on the development and persistence of asthma in children. This study aims to evaluate the clinical, immunological, and microbiological factors contributing to the persistence of asthma from preschool to school age. Methods: 183 children aged 4-8 years with chronic rhinosinusitis were enrolled in the study, including 82 children (62%) with asthma. Nasopharynx swabs were collected for microbiome analysis using next-generation sequencing methods, and nasal mucosa samples were taken to analyze mRNA expressions of predefined cytokines and innate lymphoid cells (ILCs). Out of the initial cohort, 117 children, including 74 with asthma, remained under observation for the next five years to assess asthma persistence Results: After 5 years asthma persisted in 23% (17 of 74) of patients. A multivariate model of logistic regression analysis revealed that asthma persistence was independently associated with atopy (OR=8.5, 95%CI: 1.7-43) and reduced biodiversity in the upper airway microbiome (OR=6.0, 95%CI: 1.7-22). Additionally, higher nasal expression of TSLP which correlated with IL-5 was observed in children with reduced biodiversity. In children with both atopy and reduced biodiversity higher nasal expression of IL-5 was detected, with the highest risk of persistent asthma. Conclusion: Reduced biodiversity concomitant with atopy is associated with increased risk of asthma persistence. This interaction is associated with higher nasal expression of IL-5. These findings identify new potential targets for the prevention of persistent asthma in children