Pathogen-Agnostic Tests Uncover Hidden Respiratory Risks

Researchers find undetected viruses in samples that tested negative for COVID-19 and other pathogens.

Published on Mar. 4, 2026

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Researchers from Lawrence Livermore National Laboratory and the California Department of Public Health used an untargeted metagenomic sequencing approach to identify previously undetected respiratory viruses in samples that tested negative for COVID-19 and other pathogens using standard nucleic acid amplification tests. The findings suggest pathogen-agnostic testing is a crucial complement to targeted tests like PCR, which can miss infections from unknown or emerging pathogens.

Why it matters

The COVID-19 pandemic highlighted the limitations of pathogen-specific tests, which can miss infections from unknown or emerging viruses. Pathogen-agnostic tests that analyze all genetic material in a sample can uncover hidden respiratory risks and provide more comprehensive surveillance for new and evolving pathogens.

The details

The researchers examined respiratory samples from a sentinel surveillance program in California, finding that 5% of samples that tested negative for 22 common respiratory pathogens, including SARS-CoV-2, contained a different, previously undetected virus. They also identified bacterial or fungal species in some cases. Pathogen-agnostic metagenomic sequencing provides a broader view of the pathogens present, but requires more complex equipment and is more time-consuming and costly than standard nucleic acid amplification tests.

  • The study was published on March 4, 2026.

The players

Lawrence Livermore National Laboratory

A U.S. Department of Energy national laboratory located in Livermore, California that conducts research in national security, energy, the environment, and biosciences.

California Department of Public Health

The state health department responsible for protecting public health and safety in California.

Crystal Jaing

A scientist at Lawrence Livermore National Laboratory and an author of the study.

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What they’re saying

“If a patient is infected with a life-threatening pathogen that is not covered by these tests, then this would cause a serious health risk.”

— Crystal Jaing, Scientist, Lawrence Livermore National Laboratory (Mirage News)

“Pathogen-specific assays do not provide comprehensive coverage of a broad spectrum of pathogens, while pathogen-agnostic tests provide much more information.”

— Crystal Jaing, Scientist, Lawrence Livermore National Laboratory (Mirage News)

“NAAT can be used for routine tests because they are faster and cheaper. In the COVID-19 example, a standard NAAT will give us answers right away. However, NAAT is not sufficient for surveillance of new and emerging pathogens and for future pandemic forecasting.”

— Crystal Jaing, Scientist, Lawrence Livermore National Laboratory (Mirage News)

What’s next

The researchers hope these findings will encourage public health entities to consider incorporating pathogen-agnostic approaches for detection and surveillance of respiratory illnesses.

The takeaway

Pathogen-agnostic testing using metagenomic sequencing can uncover hidden respiratory risks by detecting a broader range of viruses, bacteria, and fungi than standard nucleic acid amplification tests. This approach is a crucial complement to targeted tests like PCR for comprehensive pathogen surveillance and pandemic preparedness.