The Rise of Metagenomics in Infectious Disease

Since the mid-1990s, clinical microbiology laboratories have harnessed the power of the genome to develop faster, more sensitive diagnostic tests. Today, molecular tests such as polymerase chain reactions are a routine and valuable part of most labs.  Although molecular tests offer significant advantages over more antiquated techniques such as culture, they are still limited to a fairly narrow window of microbes that can be detected in a single sample. This means that labs may need to perform multiple blood draws from a single patient to sequentially test using several assays. And to decide what test to use and when, laboratorians must also piece together different kinds of information, including the patient’s clinical history, differential diagnosis, and local epidemiology. All of these steps can add cost, delay results, and place an unnecessary burden on the patient.

Metagenomics offers the next leap forward for infectious disease diagnostics by providing a powerful tool that can detect potentially unlimited numbers of known and novel microbes from a single sample in one test. Shotgun metagenomic sequencing enables users to easily evaluate the diversity of entire microbial populations, including novel, emerging, or uncharacterized pathogens. For the clinical microbiologist, this means the potential for truly hypothesis-free detection and quantification of all microbes in a patient sample without the need for any prior culture or growth steps. Because of its impressive diagnostic yield, shotgun metagenomics can also rapidly provide information on antimicrobial resistance genes carried by pathogens – and even human genetic information, such as host immune response – from a single sample. Importantly, it also has the potential to be deployed in early sentinel programs that can alert health systems to the emergence and transmission of novel pathogens. Never has the importance of sensitive, unbiased surveillance tools been more evident than during the COVID-19 pandemic. The earlier we can detect a problem, the more effectively we can respond.

Despite its potential, broad adoption of metagenomics hinges on our ability to clear away some of the key barriers that face clinical microbiologists today. The technical and resource demands of setting up shotgun metagenomics in the microbiology lab can be significant. Developing and deploying turnkey solutions that empower laboratorians to quickly and cost-effectively integrate metagenomics into their workflow are a must. Once microbiologists have these tools in hand, it is critical that we also provide evidence-based guidelines and protocols for validation and implementation, as well as clinical utility data to help guide testing in populations that will receive the most benefit. Labs are making headway toward this goal, as we demonstrated recently in a joint publication from scientists at Arc Bio and Stanford’s Clinical Virology Laboratory (1).

Our research compared a turnkey shotgun metagenomics platform to gold standard qPCR methods and found similar performance in terms of sensitivity, limit of detection, and viral quantification. However, unlike single-plex PCR or even syndromic PCR panels, metagenomics can interrogate a single sample for potentially thousands of microbial species and strains in a single analysis. This translates to impressively high diagnostic yield from a single blood draw. For patients where coinfections are clinically relevant, metagenomics can provide a powerful diagnostic tool to help inform and guide care. Although it remains early days, metagenomics is gaining momentum quickly and, in my view, has the potential to become the new gold standard in infectious disease diagnosis and management.