Abstract
Acute respiratory infections (ARIs) remain a leading cause of global morbidity and mortality, disproportionately affecting vulnerable populations such as children, the elderly, and immunocompromised individuals. Despite the availability of traditional diagnostic tools, including viral culture and highly elaborated PCR respiratory panels, many cases of ARI remain without an identified etiological agent. This is due to the vast diversity of viral agents that can be involved in cases of ARI, which represents a major limitation of the targeted diagnosis. In this context, viral metagenomics has emerged as a powerful, unbiased approach for detecting both known and novel pathogens directly from clinical samples. This review highlights the application of metagenomic next-generation sequencing for the investigation of etiological causes of ARIs, emphasizing its relevance in complex cases-particularly among immunocompromised patients-where standard methods might fail. We highlight the main viruses involved in respiratory infections, the strengths and limitations of metagenomic next-generation sequencing approaches, their role in genomic surveillance of respiratory viruses, and their potential to build public health responses to potentially emerging respiratory threats. Ultimately, integrating viral metagenomics into clinical and surveillance frameworks could enhance the early detection and control of respiratory viral diseases worldwide.