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Genomic insights into TB transmission networks: unveiling diagnostic delays or subclinical cases and their impact on secondary cases

S M Saleeb(1,2) C Rodríguez-Grande(1,2) S Vallejo-Godoy(3) M Martínez-Lirola(4) F Escabias(5) B Plata-Barril(1,2) M Herranz(1,2,6) S Buenestado-Serrano(1,2) P Muñoz(1,2,6,7) L Pérez Lago(1,2,6) D García de Viedma(1,2,6)

1:Servicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 2:Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.; 3:Servicio de Medicina Preventiva. Hospital Universitario Poniente de Almería, Almería, Spain.; 4:Servicio de Microbiología. Complejo Hospitalario Torrecárdenas, Almería, Spain.; 5:Area de Gestión Norte, Almería, Spain; 6:CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain; 7:Departamento de Medicina, Universidad Complutense, Madrid, Spain

Whole-genome sequencing enhances surveillance of tuberculosis (TB) transmission. A detailed analysis of SNPs distribution and case chronology in genomic networks facilitates differentiation between growing clusters due to recent transmission or reactivations. In this study, we exploit SNPs distribution within these networks to propose candidates of prolonged diagnostic delays or subclinical TB. We support these assignations on clustered cases i) genomically linked with other case/s diagnosed several years before and ii) with sequentially acquired SNPs from the case/s preceding them, suggesting the presence of viable evolving bacteria before diagnosis. We present representative clusters that underscore the differential impact of diagnostic delays on the number of secondary cases caused by them: from no impact, without secondary cases, to causing sequential consecutive infections within a household or being responsible for several community secondary cases, due to likely exposures at different stages along the diagnostic delay. In the household cluster, mono-resistance to fluoroquinolones (FQ) emerged along the diagnostic delay, due to FQ administration to treat other infections, likely causing TB monotherapy. This observation suggested that mono-resistance (monoR) might be a proxy to infer diagnostic delays/subclinical TB. Another eleven cases with monoR (2 to FQ and 9 to INH; 7 of them belonging to 4 clusters) were selected for the study. A revision of their clinical records revealed symptoms/radiological findings compatible with TB, unnoticed for a long time before diagnosis, which was consistent with our hypothesis. Funding: PI21/01823 (ISCIII); CPII20/00001 (Miguel-Servet-Contract to LPL); AP-0062-2021-C2-F2 (Junta de Andalucía); 1401/2023 (SEPAR 2023); 2021-II-PI-01 (IiSGM); COST Action-AdvanceTB (CA21164).

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