The Dawn of a New Era: Metagenomic Diagnostics for Central Nervous System Infections

Just over ten years ago, a 14-year-old boy with severe combined immunodeficiency went swimming in a freshwater lake while on vacation with his family. What followed marked the beginning of a revolution in infectious disease diagnostics.

After enjoying that swim, and the vacation with his family that surrounded it, the boy returned home and developed fever and headaches that quickly progressed to brain inflammation, seizures, and ultimately a coma. Desperate to find a treatable cause, physicians deployed more than 30 diagnostic tests – including a brain biopsy. All that testing—including blood and CSF assays—were negative.

With the boy’s condition deteriorating, a member of his care team reached out to a researcher at the University of California San Francisco (UCSF) who was working on a cutting-edge diagnostic method: metagenomic next-generation sequencing (mNGS). Made possible by the rapid advances in genomic sequencing, mNGS could evaluate all the nucleic acids in a sample, eliminating the need for a hypothesis. The premise was simple: if a pathogen was present, metagenomics could find it and use its genetic signature to identify it.

A sample of cerebrospinal fluid was sent to UCSF. Results came back with the culprit: Leptospira, an unusual type of bacteria that can be acquired after freshwater exposure. Answer in hand, appropriate antibiotic therapy was initiated and almost immediately the desperately sick child began to recover. He was discharged a month later—an outcome likely impossible without mNGS. This marked the first published case of mNGS guiding lifesaving treatment in a diagnostically challenging infection.

Now, more than a decade later, that initial case marked the beginning of a revolution in diagnostics. Delve Bio, a metagenomic sequencing laboratory, was launched with the exclusive license to the mNGS technology used to solve the Leptospira riddle in 2014. Delve Bio has moved mNGS sequencing from the lab into the clinic through its flagship testing service, Delve Detect, which delivers 22 percent greater diagnostic yield than conventional testing and provides results in just 48 hours – giving physicians the ability to get effective treatment to some of their sickest patients faster.

The Diagnostic Challenge of CNS Infections

Less than half of patients with bacterial meningitis exhibit the classic symptoms of fever, neck stiffness, and altered mental status. Clinicians identify the culprit in fewer than half of all cases. There are two primary reasons. First, the causative pathogen is not considered or the wrong tests are ordered and second, conventional testing relies on pathogen-specific hypotheses and do not include all possible pathogen types, making atypical infections easy to miss. Metagenomics solves these problems by enabling detection of any infectious organism with a single test.

The diagnostic uncertainty from conventional test methods comes at a cost. Delayed or missed diagnoses can lead to irreversible neurological damage, prolonged hospital stays, ICU admissions, or even death.

Typical diagnostic workups for suspected CNS infections include 25 to 30 laboratory tests—from Gram stains and cultures to PCR panels and antigen tests— yet often this barrage of testing yields no answers. Stepwise or serial testing, combined with reliance on clinician suspicion, can trigger cascading diagnostic delays. Even multiplex PCR panels typically test for just 10–20 pathogens, leaving out hundreds of potential causes.

One thing is clear: better diagnostic tests are needed, and metagenomics offers a solution to the problem of missed diagnoses.

mNGS: A Hypothesis-Free Diagnostic Powerhouse

mNGS testing with Delve Detect delivers both a powerful diagnostic tool and a simpler clinical workup by offering a comprehensive, unbiased pathogen identification in a single sample. Unlike traditional tests that target specific pathogens, Delve Detect sequences and analyzes all nucleic acids (DNA and RNA) present in a cerebrospinal fluid sample—including bacteria, viruses, fungi, and parasites – against a database of more than 68,000 potential pathogens, all within 48 hours.

• Increase diagnostic yield: multiple studies have shown mNGS delivers 22% greater diagnostic yield over traditional testing.
• Culture independence: Detects organisms that fail to grow in standard cultures.
• Broad utility: Effective in immunocompromised patients and cases with atypical presentations.
• Detection of co-infections and novel pathogens: Captures complex infections often missed by conventional tests.

The mNGS diagnostic approach has a strong base of evidence showing the clinical utility of, the technology from UCSF – now Delve – that originally diagnosed Leptospira in the 2014 case. In November 2024, a retrospective review of over 4,800 samples over 7 years showed that technology behind Delve Detect delivered 22% greater diagnostic yield, where mNGS was the only test that identified the causative pathogen. Importantly, these studies also show that mNGS diagnoses inform care: in 38% of cases, mNGS results changed patient management, including initiation of targeted therapy or cessation of unnecessary treatments.

Streamlining the clinical workup and getting patients to the right treatment faster is also important for reducing the cost of treating meningitis/encephalitis. Cases to meningitis and encephalitis that involve ICU admission or delayed lumbar puncture can spiral to more $200,000. Rapid, accurate diagnosis through mNGS helps offset these costs by streamlining care pathways and improving resource allocation.

Redefining the Diagnostic Standard

In the last 10 years, Delve Detect has grown from a research technology used as a last resort into a robust, clinically validated, and commercially available platform that addresses the blind spots of conventional testing. In the diagnosis of CNS infections—where time is critical and diagnostic uncertainty is the norm—mNGS offers a powerful solution. Its ability to detect the undetectable, shorten diagnostic odysseys, and improve patient outcomes makes it not just a promising research tool, but an essential one for modern infectious disease care.

As more healthcare systems adopt this technology, mNGS has the potential to become the standard of care for difficult-to-diagnose infections—turning clinical mystery into diagnostic clarity, and delayed treatments into saved lives.