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Biomarkers could predict AFM with more than 80% accuracy

Photo of Benjamin Briggs
Benjamin J. Briggs

WASHINGTON — Researchers identified a biological signature of acute flaccid myelitis, or AFM, found in cerebrospinal fluid.

The findings, presented at IDWeek, also allowed researchers to distinguish between the specific enteroviruses that have been associated with AFM.

“There is, in fact, a signature of AFM, or there is a profile in the transcriptome of AFM patients, that seems different than other neurological processes that we have evaluated using this test,” Benjamin J. Briggs, MD, PhD, junior faculty member at the University of California, San Francisco, told Infectious Diseases in Children. “We have looked at about 1,500 patients using this test. We found that AFM patients seem to have a unique signature that differs from a bacterial infection or even a viral infection.”

Briggs added that AFM appears to be a “complex interaction between virus and host, and we still need to sort out some of the details.”

The CDC began investigating AFM in 2014 after 120 confirmed cases were reported in 34 states. The number of cases tends to spike every 2 years, with 235 cases reported in 41 states during 2018 and just 20 cases reported in nine states this year.

More than 90% of these cases had mild respiratory illness or fever before developing signs and symptoms of AFM, which can usually include sudden arm or leg weakness and loss of muscle tone and reflexes leading to paralysis. Some people, the CDC reported, may also experience facial droop, difficulty with eye movement, as well as arm and leg pain.

To identify these potential biomarkers, the researchers analyzed approximately 130 cerebrospinal fluid (CSF) samples. They performed RNA sequencing to examine host responses. This information helped them classify patients based on potential AFM causes, including enterovirus D-68 (EV-D68), EV-A71, West Nile virus and Powassan virus.

According to Briggs and colleagues, a specific AFM signature was identified in 21 CSF samples. The signature, they said, predicted potential viral links to AFM with more than 80% accuracy in blinded test samples.

The CSF factors that most accurately distinguished between EV-D68- and EV-A71-associated AFM included protein targeting, viral transcription, viral gene expression and translation initiation pathways.

The researchers proposed that this strategy could assist with early diagnosis of AFM, which could improve the use of targeted treatments.

However, Briggs said the test is “fairly specialized,” and its use in a clinical setting may not be feasible at this time.

“Unfortunately, I think because of the technical issues involved with doing the sequencing and analysis, I don’t foresee it being a rapidly deployable solution that would be used everywhere,” he said. “The good news is that the NIH has formed a coalition of researchers to study this in anticipation of a future outbreak. If there is another outbreak of AFM as expected in 2020, we would be part of that NIH consortium, and we are looking forward to be able to try to help out with those cases.” – by Katherine Bortz

References:

Briggs BJ, et al. Abstract LB14. Presented at: IDWeek; Oct. 2-6, 2019; Washington.

CDC. Acute flaccid myelitis: AFM investigation. https://www.cdc.gov/acute-flaccid-myelitis/afm-investigation.html. Accessed Oct. 1, 2019.

CDC. Acute flaccid myelitis: Cases in the U.S. https://www.cdc.gov/acute-flaccid-myelitis/cases-in-us.html#cases-by-year. Accessed Oct. 1, 2019.

CDC. Acute flaccid myelitis: Symptoms. https://www.cdc.gov/acute-flaccid-myelitis/symptoms.html. Accessed Oct. 1, 2019.

CDC. Non-polio enterovirus: About enterovirus A71. https://www.cdc.gov/non-polio-enterovirus/about/ev-a71.html. Accessed Oct. 3, 2019.

CDC. Non-polio enterovirus: About enterovirus D68. https://www.cdc.gov/non-polio-enterovirus/about/ev-d68.html. Accessed Oct. 3, 2019.

Disclosures: Briggs reports that his lab is funded by Abbott Laboratories.

Photo of Benjamin Briggs
Benjamin J. Briggs

WASHINGTON — Researchers identified a biological signature of acute flaccid myelitis, or AFM, found in cerebrospinal fluid.

The findings, presented at IDWeek, also allowed researchers to distinguish between the specific enteroviruses that have been associated with AFM.

“There is, in fact, a signature of AFM, or there is a profile in the transcriptome of AFM patients, that seems different than other neurological processes that we have evaluated using this test,” Benjamin J. Briggs, MD, PhD, junior faculty member at the University of California, San Francisco, told Infectious Diseases in Children. “We have looked at about 1,500 patients using this test. We found that AFM patients seem to have a unique signature that differs from a bacterial infection or even a viral infection.”

Briggs added that AFM appears to be a “complex interaction between virus and host, and we still need to sort out some of the details.”

The CDC began investigating AFM in 2014 after 120 confirmed cases were reported in 34 states. The number of cases tends to spike every 2 years, with 235 cases reported in 41 states during 2018 and just 20 cases reported in nine states this year.

More than 90% of these cases had mild respiratory illness or fever before developing signs and symptoms of AFM, which can usually include sudden arm or leg weakness and loss of muscle tone and reflexes leading to paralysis. Some people, the CDC reported, may also experience facial droop, difficulty with eye movement, as well as arm and leg pain.

To identify these potential biomarkers, the researchers analyzed approximately 130 cerebrospinal fluid (CSF) samples. They performed RNA sequencing to examine host responses. This information helped them classify patients based on potential AFM causes, including enterovirus D-68 (EV-D68), EV-A71, West Nile virus and Powassan virus.

According to Briggs and colleagues, a specific AFM signature was identified in 21 CSF samples. The signature, they said, predicted potential viral links to AFM with more than 80% accuracy in blinded test samples.

The CSF factors that most accurately distinguished between EV-D68- and EV-A71-associated AFM included protein targeting, viral transcription, viral gene expression and translation initiation pathways.

The researchers proposed that this strategy could assist with early diagnosis of AFM, which could improve the use of targeted treatments.

However, Briggs said the test is “fairly specialized,” and its use in a clinical setting may not be feasible at this time.

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“Unfortunately, I think because of the technical issues involved with doing the sequencing and analysis, I don’t foresee it being a rapidly deployable solution that would be used everywhere,” he said. “The good news is that the NIH has formed a coalition of researchers to study this in anticipation of a future outbreak. If there is another outbreak of AFM as expected in 2020, we would be part of that NIH consortium, and we are looking forward to be able to try to help out with those cases.” – by Katherine Bortz

References:

Briggs BJ, et al. Abstract LB14. Presented at: IDWeek; Oct. 2-6, 2019; Washington.

CDC. Acute flaccid myelitis: AFM investigation. https://www.cdc.gov/acute-flaccid-myelitis/afm-investigation.html. Accessed Oct. 1, 2019.

CDC. Acute flaccid myelitis: Cases in the U.S. https://www.cdc.gov/acute-flaccid-myelitis/cases-in-us.html#cases-by-year. Accessed Oct. 1, 2019.

CDC. Acute flaccid myelitis: Symptoms. https://www.cdc.gov/acute-flaccid-myelitis/symptoms.html. Accessed Oct. 1, 2019.

CDC. Non-polio enterovirus: About enterovirus A71. https://www.cdc.gov/non-polio-enterovirus/about/ev-a71.html. Accessed Oct. 3, 2019.

CDC. Non-polio enterovirus: About enterovirus D68. https://www.cdc.gov/non-polio-enterovirus/about/ev-d68.html. Accessed Oct. 3, 2019.

Disclosures: Briggs reports that his lab is funded by Abbott Laboratories.

    Perspective
    Matthew J. Elrick

    Matthew J. Elrick

    AFM is challenging to diagnose accurately because the putative causal viruses can only rarely be identified in the CSF, and no objective biomarkers exist. Currently, the diagnosis of AFM is made on a clinical and radiologic basis and remains ambiguous or uncertain in a significant subset of patients.

    To address this problem, Briggs and colleagues proposed a novel biomarker based on transcriptomic analysis of patient CSF samples. They identified a transcriptional signature associated with AFM that presumably represents the host response to infection. Further, they identified features of the signature that distinguish between viral species.

    This innovative approach may ultimately prove valuable for biomarker-based clinical diagnosis of AFM, though much work remains to demonstrate the validity of such a test.  Importantly, this approach also has the potential to strengthen the evidence linking AFM to enteroviruses by demonstrating signs of infection by specific viral species even when the virus itself cannot be isolated.

    • Matthew J. Elrick, MD, PhD
    • Assistant professor
      Pediatric neurology and neuromuscular medicine
      Johns Hopkins School of Medicine

    Disclosures: Elrick reports no relevant financial disclosures.

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