Novel Sequencing Test to Uncover Mystery Causes of Brain Inflammation Now Available at UCSF

Physicians seeking a cause for tough-to-diagnose cases of encephalitis or meningitis have a new tool in their arsenal, thanks to scientists at UC San Francisco’s Center for Next-Gen Precision Diagnostics. With a novel clinical test called metagenomic next-generation sequencing (mNGS), it is now possible to bypass a time-consuming battery of specific tests and look more broadly for a wide array of pathogens all at once.

Using DNA and RNA obtained from a patient’s spinal fluid, the mNGS assay looks at the totality of possible infectious agents, including bacteria, viruses, fungi and parasites, thus eliminating the need for physicians to work from a predetermined list of suspected organisms. The broad-spectrum test can help ascertain if the patient’s neurological symptoms are caused by a specific pathogen; if no infection is identified, the results may guide physicians toward working up an autoimmune or other noninfectious condition. Such findings can help physicians determine the best treatment – and avoid providing therapies that are ineffective or potentially harmful to the patient.

“The mNGS test upends the typical approach to searching for the causes of brain inflammation that are challenging to diagnose,” says Charles Chiu, MD, PhD, professor of Laboratory Medicine and Medicine at UCSF and director of the UCSF-Abbott Viral Diagnostics and Discovery Center. “Physicians can use the test to simultaneously search for virtually every organism – basically to find the needle in the haystack.” Typically, patients undergo 30-50 tests to find a cause, and yet in about half of all cases the diagnosis is missed.

Clinical Study Showed Advantage of mNGS Testing

In a 2019 study published in the New England Journal of Medicine, UCSF scientists used mNGS testing to analyze the spinal fluid of 204 hospitalized patients whose diagnosis for encephalitis, meningitis or myelitis was inconclusive. The test found many of the same infections that conventional testing identified, but also 13 additional infections that had been missed previously. In more than half of those 13 cases, the diagnosis directly impacted the patient’s treatment.

“Our study showed the benefit of mNGS testing over conventional culture or other tests,” says Chiu, the study’s senior author. “Moreover, the test can yield results in as soon as 48 hours.”

“Encephalitis and meningitis cases present one of the greatest diagnostic challenges in neurology,” says Michael Wilson, MD, MAS, associate professor of Neurology at UCSF’s Weill Institute for Neurosciences and a co-first author of the 2019 study. “Adding to physicians’ frustration is that time is of the essence in treating these illnesses, so finding an underlying cause as quickly as possible is critical. The mNGS test can prevent a wild goose chase of testing, and a succession of treatments that not only may not work but could be counterproductive.”

The mNGS test has been validated in a licensed Clinical Laboratory Improvement Amendments (CLIA) lab at UCSF for patient testing and has been designated by the United States Food and Drug Administration (FDA) as a breakthrough device; the UCSF team is in the process of seeking FDA approval. Currently UCSF is the only academic institution in the U.S. routinely offering mNGS testing of spinal fluid for diagnosis of neurological infections, including meningitis, encephalitis and myelitis.

Earlier Testing Could Bring Greater Success

Although at present the mNGS test is administered primarily on hospitalized patients, often as a last resort, the UCSF scientists believe that it holds promise for patients earlier in their diagnostic journey. “We think mNGS can be attractive as a first-line test, resulting in quicker diagnosis and faster, more successful treatment,” says Chiu. “It might also be more cost-effective, reducing the need for exhaustive testing that might go nowhere, and help patients to recover more quickly as a result of more timely and accurate diagnoses.”

“We now have a better understanding of who is most likely to benefit from mNGS testing and can consult with physicians about whether this test makes sense for their patients,” says Wilson. “For many patients suffering with these terribly debilitating illnesses, hastening a broader search for a cause could reduce their anxiety and possibly save their lives.”

Physicians interested in having their patient’s sample tested at UCSF’s Center for Next-Gen Precision Diagnostics can find information about ordering the test here: https://nextgendiagnostics.ucsf.edu/providers/

mNGS Testing Identifies Rare Bacterium as Source of Encephalitis

Josh was a 14-year-old boy from Wisconsin whose encephalitis did not respond to all empiric treatments. He was thought to have contracted the disease while on vacation in Puerto Rico, and doctors had ordered about 100 tests, including a brain biopsy, all of which proved inconclusive. Josh endured three hospitalizations in four months and spent 44 days in the ICU – part of that time in a medically induced coma. After UCSF researchers conducted mNGS testing from a sample obtained from Josh’s spinal fluid, they diagnosed him with neuroleptosperosis, which was caused by Leptospira santorosai, a bacterium typically found in lakes or streams in the developing world. Because of its rarity in the U.S., it was not on the differential diagnosis for his treating physicians. The treatment of choice for this disease is penicillin – one of the few antibiotics that Josh had not been given. He has since made a full recovery.

“Josh’s story highlights the importance of having a broad-based test that doesn’t rely on a predetermined set of potential organisms,” says Chiu.