In the Journals

Metagenomic sequencing improves diagnosis of neurologic infections

Charles Chiu, MD
Charles Chiu

Metagenomic next-generation sequencing, or NGS, of cerebrospinal fluid can improve the diagnosis of neurologic infections in patients with encephalitis or meningitis, according to findings from a 1-year, multicenter, prospective study published in The New England Journal of Medicine.

During the study, metagenomic NGS identified some infections that clinical testing missed, leading to adjusted treatment in some cases, researchers reported.

“A new clinical metagenomic sequencing test of cerebrospinal fluid is able to diagnose mysterious neurological illnesses in patients that are missed by conventional approaches,” Charles Chiu, MD, PhD, director of University of California, San Francisco’s Abbott Viral Diagnostics and Discovery Center, told Infectious Disease News.

“The metagenomic next-generation sequencing test is a comprehensive test that looks for nucleic acid (DNA and RNA) from all potential pathogens — bacteria, viruses, fungi and parasites. It may be particularly useful for diagnosing neurological infections from organisms that do not grow or grow poorly in culture (eg, viruses, fungi, atypical bacteria such as Nocardia) or rare organisms that are not commonly considered in the differential diagnosis (eg, parasites such as Angiostrongylus cantonensis and Balamuthia mandrillaris, viruses such as St. Louis encephalitis virus and hepatitis E virus).”

According to Chiu and colleagues, the traditional approach to diagnosing neuroinflammatory diseases presents difficulties because of overlapping clinical manifestations of infectious and noninfectious causes, the limited availability and volume of central nervous system samples obtained through invasive procedures and a lack of diagnostic tests for rare pathogens. Because of these challenges, a cause is not identified in half of acute meningoencephalitis cases, they said.

To address this diagnostic need, the researchers enrolled 204 adult and pediatric patients from eight hospitals who presented with idiopathic meningitis with or without encephalitis or myelitis, or both. According to Chiu and colleagues, many patients were severely ill, with 48.5% having been admitted to the ICU. Patients in the study had a 30-day mortality rate of 11.3%, they reported.

Physicians diagnosed 58 infections of the nervous system in 57 patients (27.9%). According to the study, metagenomic NGS identified 13 (22%) infections that were not identified by clinical testing at the source hospital. Out of these 13 diagnoses, eight had a “likely clinical effect,” and seven resulted in treatment adjustments by physicians, the researchers found.

“The highest diagnostic yield resulted from a combination of metagenomic NGS of [cerebrospinal fluid] and conventional testing, including serologic testing and testing of sample types other than [cerebrospinal fluid],” Chiu and colleagues wrote.

They concluded that clinical metagenomic NGS of cerebrospinal fluid “represents a potential step forward in the diagnosis of meningoencephalitis,” and that it “may guide earlier and more targeted treatments for neuroinvasive infections, identify emerging infections and disease phenotypes, and accelerate the workup and treatment for noninfectious causes.”

“We were amazed by the sheer number of additional diagnoses that were successfully made using the metagenomic NGS test, as the patient cohort that we investigated was largely [composed] of cases of ‘last resort,’ with patients already having undergone extensive testing in tertiary care hospitals prior to enrollment,” Chiu said. “Also, we were surprised to find that the metagenomic NGS test as a single test was clinically useful in diagnosing infections in critically ill patients.” – by Joe Gramigna

Disclosures: Chiu reports receiving grants from numerous institutions and having several related patents pending. Please see the study for all other authors’ relevant financial disclosures.

Charles Chiu, MD
Charles Chiu

Metagenomic next-generation sequencing, or NGS, of cerebrospinal fluid can improve the diagnosis of neurologic infections in patients with encephalitis or meningitis, according to findings from a 1-year, multicenter, prospective study published in The New England Journal of Medicine.

During the study, metagenomic NGS identified some infections that clinical testing missed, leading to adjusted treatment in some cases, researchers reported.

“A new clinical metagenomic sequencing test of cerebrospinal fluid is able to diagnose mysterious neurological illnesses in patients that are missed by conventional approaches,” Charles Chiu, MD, PhD, director of University of California, San Francisco’s Abbott Viral Diagnostics and Discovery Center, told Infectious Disease News.

“The metagenomic next-generation sequencing test is a comprehensive test that looks for nucleic acid (DNA and RNA) from all potential pathogens — bacteria, viruses, fungi and parasites. It may be particularly useful for diagnosing neurological infections from organisms that do not grow or grow poorly in culture (eg, viruses, fungi, atypical bacteria such as Nocardia) or rare organisms that are not commonly considered in the differential diagnosis (eg, parasites such as Angiostrongylus cantonensis and Balamuthia mandrillaris, viruses such as St. Louis encephalitis virus and hepatitis E virus).”

According to Chiu and colleagues, the traditional approach to diagnosing neuroinflammatory diseases presents difficulties because of overlapping clinical manifestations of infectious and noninfectious causes, the limited availability and volume of central nervous system samples obtained through invasive procedures and a lack of diagnostic tests for rare pathogens. Because of these challenges, a cause is not identified in half of acute meningoencephalitis cases, they said.

To address this diagnostic need, the researchers enrolled 204 adult and pediatric patients from eight hospitals who presented with idiopathic meningitis with or without encephalitis or myelitis, or both. According to Chiu and colleagues, many patients were severely ill, with 48.5% having been admitted to the ICU. Patients in the study had a 30-day mortality rate of 11.3%, they reported.

Physicians diagnosed 58 infections of the nervous system in 57 patients (27.9%). According to the study, metagenomic NGS identified 13 (22%) infections that were not identified by clinical testing at the source hospital. Out of these 13 diagnoses, eight had a “likely clinical effect,” and seven resulted in treatment adjustments by physicians, the researchers found.

“The highest diagnostic yield resulted from a combination of metagenomic NGS of [cerebrospinal fluid] and conventional testing, including serologic testing and testing of sample types other than [cerebrospinal fluid],” Chiu and colleagues wrote.

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They concluded that clinical metagenomic NGS of cerebrospinal fluid “represents a potential step forward in the diagnosis of meningoencephalitis,” and that it “may guide earlier and more targeted treatments for neuroinvasive infections, identify emerging infections and disease phenotypes, and accelerate the workup and treatment for noninfectious causes.”

“We were amazed by the sheer number of additional diagnoses that were successfully made using the metagenomic NGS test, as the patient cohort that we investigated was largely [composed] of cases of ‘last resort,’ with patients already having undergone extensive testing in tertiary care hospitals prior to enrollment,” Chiu said. “Also, we were surprised to find that the metagenomic NGS test as a single test was clinically useful in diagnosing infections in critically ill patients.” – by Joe Gramigna

Disclosures: Chiu reports receiving grants from numerous institutions and having several related patents pending. Please see the study for all other authors’ relevant financial disclosures.