Cover Story

Health officials on ‘high alert’ for AFM in 2020

In 2014, there was an unexpected surge in the number of children in the United States who experienced sudden unexplained limb weakness and paralysis, particularly after a viral illness. The seemingly new condition, now recognized as acute flaccid myelitis, or AFM, is a subset of acute flaccid paralysis.

CDC surveillance data show a spike in AFM cases occurring every other year. Most recently, there were 237 cases reported in 2018 and 33 cases reported in 2019. If this pattern continues, physicians in the U.S. should be prepared for another potential increase in AFM cases this year, experts said.

Kevin Messacar, MD, a pediatric infectious disease physician at Children’s Hospital Colorado, said the acute onset of limb weakness or unexplained weakness in the muscles of the face or throat, especially following a febrile illness, should raise concerns about the possibility of acute flaccid myelitis in children.

Source: Children’s Hospital Colorado

“While no one can predict the future, there’s been a distinct seasonal biennial pattern to AFM outbreaks coming in the summer to fall of even-numbered years since 2014,” Kevin Messacar, MD, pediatric infectious disease physician and researcher at Children’s Hospital Colorado and the University of Colorado, told Infectious Diseases in Children.

“We need to be as prepared as possible for AFM to return in 2020 or beyond. There are people trying to get the best predictive data we can, but regardless of that, there’s never a perfect prediction of these types of diseases. However, the repeating pattern would suggest that we need to really work hard to prepare in case it does come back.”

Infectious Diseases in Children spoke with Messacar and other experts about what clinicians need to know to be prepared for another epidemic year for AFM.

Mysterious outbreaks

AFM can be caused by several viruses, including enteroviruses — such as poliovirus — flaviviruses, as well as noninfectious disorders like transverse myelitis, according to Janell Routh, MD, MHS, a medical officer in the CDC’s Division of Viral Diseases.

“But the question that we are really trying to answer is what is causing those peaks?” she said in an interview. “Is it a single virus like an enterovirus that causes that surge every other year? Or are there multiple etiologies involved with that surge?”

According to the CDC, evidence indicates that more than 90% of patients with AFM had a mild respiratory illness or fever before developing symptoms. Furthermore, the outbreaks seen in even-numbered years appeared to follow the same pattern as the circulation of enterovirus D68 (EV-D68) — making it the prime suspect for what may be causing the seasonal waves, according to Messacar.

The evidence to support this association is not just temporal, Routh noted.

“One of the most recent interesting pieces of evidence has come from the discovery of enterovirus antibodies in the cerebrospinal fluid (CSF) of AFM patients,” she said.

Anthony S. Fauci

In a recent study published in mBio, researchers analyzed the CSF of 14 patients with AFM and five controls with other central nervous system diseases and found the presence of antibodies to enterovirus peptides in most patients with AFM (n = 11; 79%). Comparatively, the prevalence of antibodies to enterovirus peptides was significantly lower in non-AFM patients (n = 1 of 5; 20%), adults with other non-AFM central nervous system diseases (n = 2 of 11; 18%) and children with Kawasaki disease (n = 0 of 10). Additionally, peptides to EV-D68 were commonly observed in patients with AFM (CSF: n = 6 of 14 [43%]; serum samples: n = 8 of 11 [73%]).

Additionally, another study published in Nature Medicine reported that nearly 70% of patients with AFM tested positive for viral antibodies of enterovirus origin.

These results support a plausible link between enteroviruses — particularly EV-D68 — and AFM, Routh said.

“These two studies have really helped move the needle toward being a little more definitive in thinking that enteroviruses are indeed a main cause of the AFM outbreaks,” Matthew R. Vogt, MD, PhD, pediatric infectious diseases fellow at Monroe Carell Jr. Children’s Hospital at Vanderbilt, told Infectious Diseases in Children. “That being said, there are other viruses that are not enteroviruses that can certainly cause AFM.”

However, it remains unclear how such a ubiquitous virus is causing AFM, Routh said.

“Enteroviruses circulate every year, so what is it about this certain very small group of people who rather than recovering from a mild viral virus go on to develop paralysis?” she wondered.

Uncovering the answer to that question will be pivotal to developing ways to prevent and treat AFM, according to Routh.

Prevention and treatment challenges

Experts are in the beginning stages of developing a vaccine against EV-D68, assuming that the virus causes AFM, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in an interview.

Janell Routh

“But when you have so few cases each year — as tragic as it is for the children who get it — it occurs in only one in a million people. When something occurs in one in a million people, it’s kind of tough to get a vaccine that would be deployable to anybody because you won’t know who to vaccinate,” Fauci said. “If AFM explodes in 2020 or 2022 into something much more prevalent like we saw with polio, then the issue of a vaccine will become much more relevant.”

Currently, there is no vaccine for the viruses most often associated with AFM, so general infection prevention strategies, such as good hygiene, staying home when sick, covering the mouth when coughing and sneezing and washing hands regularly, can be helpful in keeping children safe, Messacar said.

In addition to vaccine development, researchers are creating therapeutics for AFM, Vogt said.

“However, one big challenge is that AFM is a clinical syndrome that seems to have many different pathways that contribute to it — it’s not just one enterovirus and it’s not even just enteroviruses,” he said. “There are many different ways that AFM can be triggered. So, if we make a therapy that targets one of these particular viruses, there will still be other viruses that wouldn’t be targeted by that therapy.”

So far, the main treatment available for children with AFM is aggressive physical and occupational therapy, according to Vogt.

“Rehabilitation may mitigate some of the effects of the paralytic syndrome,” Fauci said.

Vogt and colleagues are currently developing human monoclonal antibodies to treat infections from viruses associated with AFM. Vogt said therapeutics such as fluoxetine and IV immunoglobulin have shown promise in lab tests and mice but not in humans with AFM.

Researchers recently identified a unique biological signature of AFM in CSF that could potentially aid in early diagnosis and, thus, improve the use of targeted treatments.

Matthew R. Vogt

The research, which was presented at IDWeek 2019, used RNA sequencing to evaluate host responses in CSF samples and classify possible AFM causes, such as EV-D68, EV-A71, West Nile virus and Powassan virus. Twenty-one of 130 CSF samples demonstrated a specific AFM signature.

Protein targeting, viral transcription, viral gene expression and translation initiation pathways were the CSF factors that most precisely differentiated between EV-D68- and EV-A71-associated AFM.

The signature predicted viral links to AFM with more than 80% accuracy but is “fairly specialized,” so its use in a clinical setting is not likely yet, according to the researchers.

“Once we begin to understand more about the pathogenesis, we can then move forward to treatment and prevention strategies,” Routh said. “I’m really hoping that in the next year we will be able to speak more clearly and have more evidence to support treatment for this illness.”

What to look for

It is important that clinicians are aware of AFM and its distinctive clinical presentations, Messacar said.

“AFM is a rare disease, but at the same time, it’s an incredibly serious disease that shouldn’t be missed,” Routh said.

Acute onset of limb weakness in an arm or leg or unexplained weakness in the muscles of the face or throat — particularly following a febrile illness — should raise concern that the underlying cause may be AFM, and any child presenting with these symptoms should undergo a diagnostic work-up for AFM, according to Messacar.

David Kimberlin

Clinicians should be especially aware of these signs during the late summer to early fall months in even-numbered years, Vogt noted, although AFM can occur at any time. Since there is no therapy to prevent the progression of AFM and the disease can progress quickly over just a day or two, early recognition and hospitalization is key to getting children the supportive care they need if paralysis becomes life-threatening and affects the muscles that control swallowing or breathing, he added.

“There is no therapy that prevents the progression of paralysis,” Vogt said. “The need for hospitalization is because of how rapidly AFM can progress and if severe, the patients will need supportive care.”

If AFM is suspected, clinicians should collaborate with neurologic and infectious diseases specialists to diagnose the patient, Routh noted.

“There have been many children in past outbreaks who have had a delayed diagnosis due to weakness being attributed to another cause like a musculoskeletal trauma or a nerve injury when really that was due to spinal cord inflammation due to AFM,” Messacar said. “Knowing that AFM is a possibility, and knowing the differences between just fatigue or myalgias that can occur with influenza compared with localized flaccid or hypotonic weakness, is important to differentiate AFM from other common fatigues that can happen with other viral illnesses.”

To confirm a diagnosis of AFM, limb weakness indicative of AFM should be assessed with a lumbar puncture and MRI of the brain and spine, he noted.

“Once a diagnosis of AFM is confirmed, clinicians should be looking for what could have triggered or caused the condition,” Messacar said.

Prompt collection of biologic specimens by swabbing the back of the nose and throat, and obtaining the spinal fluid, blood samples and stool samples is important to help advance the understanding of what is causing AFM and understand clinical phenotypes and prognosis associated with specific pathogens, according to Messacar.

‘On high alert’

In addition to the CDC and NIH, there is an AFM working group — “a self-organized collection of clinicians of all sorts” — working on trying to solve AFM, according to Vogt.

“The United States is more prepared now for an outbreak of AFM than ever,” he said.

In the event that the U.S. experiences another surge of AFM cases in 2020, the CDC will immediately host a Clinician Outreach and Communications Activity (COCA) call to rapidly communicate urgent information to clinical providers, Routh said.

“We really are on high alert right now for a possibility of an outbreak in 2020, which we were not in past years because we weren’t even sure what we were dealing with,” Fauci said.

Although the U.S. is better equipped for another outbreak of AFM in 2020, AFM remains unique, and there is still much to learn about the disease, according to Routh. She said the NIH and the CDC are collaborating to study the natural history of the disease.

“This study will advance our understanding of the disease and create a biorepository that will promote additional AFM research in the future,” David Kimberlin, MD, an ex officio member of the AAP Committee on Infectious Diseases and principal investigator of the NIH study on AFM, told Infectious Diseases in Children.

Patients with limb weakness who are suspected of having AFM will be enrolled in the study and followed at regular intervals through the course of their hospitalization and up to a year after their hospitalization for follow-up, according to Routh.

The study will assess patients across a wide geographic region in the U.S. and other countries, including Canada, England and Peru, Vogt said. Members of the patients’ households who have been infected with the same viruses but did not get AFM will act as the controls in the study, he said.

“This study looks to be very key in helping us try to identify what factors influence why one patient gets AFM while everyone else in their family are only mildly affected with these respiratory illnesses,” Vogt said.

The study of the natural history of AFM will be the first opportunity to get standardized data on different treatment modalities for AFM and link those to outcomes, according to Routh.

“Right now, we don’t have an armamentarium of tools to be able to slow or stop the outbreak like we do with other diseases, such as measles,” she said. “The one thing that we really can do is target and improve patient care by letting clinicians know about AFM, know that we are seeing cases and put information out there so that they can easily recognize and hospitalize these patients. Our community does believe that with early access to care and intervention, we may be able to change outcomes for these children.” – by Alaina Tedesco

Disclosures: Fauci, Messacar and Routh report no relevant financial disclosures. Kimberlin reports being the principal investigator of the NIH natural history study of AFM, which is funded through awards received by his university from the NIAID. Vogt reports being an inventor on a patent application for a human monoclonal antibody being developed as a potential therapeutic specifically for EV-D68.

Click here to read the Point/Counter "Are enteroviruses the predominant cause of AFM in the US?"

In 2014, there was an unexpected surge in the number of children in the United States who experienced sudden unexplained limb weakness and paralysis, particularly after a viral illness. The seemingly new condition, now recognized as acute flaccid myelitis, or AFM, is a subset of acute flaccid paralysis.

CDC surveillance data show a spike in AFM cases occurring every other year. Most recently, there were 237 cases reported in 2018 and 33 cases reported in 2019. If this pattern continues, physicians in the U.S. should be prepared for another potential increase in AFM cases this year, experts said.

Kevin Messacar, MD, a pediatric infectious disease physician at Children’s Hospital Colorado, said the acute onset of limb weakness or unexplained weakness in the muscles of the face or throat, especially following a febrile illness, should raise concerns about the possibility of acute flaccid myelitis in children.

Source: Children’s Hospital Colorado

“While no one can predict the future, there’s been a distinct seasonal biennial pattern to AFM outbreaks coming in the summer to fall of even-numbered years since 2014,” Kevin Messacar, MD, pediatric infectious disease physician and researcher at Children’s Hospital Colorado and the University of Colorado, told Infectious Diseases in Children.

“We need to be as prepared as possible for AFM to return in 2020 or beyond. There are people trying to get the best predictive data we can, but regardless of that, there’s never a perfect prediction of these types of diseases. However, the repeating pattern would suggest that we need to really work hard to prepare in case it does come back.”

Infectious Diseases in Children spoke with Messacar and other experts about what clinicians need to know to be prepared for another epidemic year for AFM.

Mysterious outbreaks

AFM can be caused by several viruses, including enteroviruses — such as poliovirus — flaviviruses, as well as noninfectious disorders like transverse myelitis, according to Janell Routh, MD, MHS, a medical officer in the CDC’s Division of Viral Diseases.

“But the question that we are really trying to answer is what is causing those peaks?” she said in an interview. “Is it a single virus like an enterovirus that causes that surge every other year? Or are there multiple etiologies involved with that surge?”

According to the CDC, evidence indicates that more than 90% of patients with AFM had a mild respiratory illness or fever before developing symptoms. Furthermore, the outbreaks seen in even-numbered years appeared to follow the same pattern as the circulation of enterovirus D68 (EV-D68) — making it the prime suspect for what may be causing the seasonal waves, according to Messacar.

PAGE BREAK

The evidence to support this association is not just temporal, Routh noted.

“One of the most recent interesting pieces of evidence has come from the discovery of enterovirus antibodies in the cerebrospinal fluid (CSF) of AFM patients,” she said.

Anthony S. Fauci

In a recent study published in mBio, researchers analyzed the CSF of 14 patients with AFM and five controls with other central nervous system diseases and found the presence of antibodies to enterovirus peptides in most patients with AFM (n = 11; 79%). Comparatively, the prevalence of antibodies to enterovirus peptides was significantly lower in non-AFM patients (n = 1 of 5; 20%), adults with other non-AFM central nervous system diseases (n = 2 of 11; 18%) and children with Kawasaki disease (n = 0 of 10). Additionally, peptides to EV-D68 were commonly observed in patients with AFM (CSF: n = 6 of 14 [43%]; serum samples: n = 8 of 11 [73%]).

Additionally, another study published in Nature Medicine reported that nearly 70% of patients with AFM tested positive for viral antibodies of enterovirus origin.

These results support a plausible link between enteroviruses — particularly EV-D68 — and AFM, Routh said.

“These two studies have really helped move the needle toward being a little more definitive in thinking that enteroviruses are indeed a main cause of the AFM outbreaks,” Matthew R. Vogt, MD, PhD, pediatric infectious diseases fellow at Monroe Carell Jr. Children’s Hospital at Vanderbilt, told Infectious Diseases in Children. “That being said, there are other viruses that are not enteroviruses that can certainly cause AFM.”

However, it remains unclear how such a ubiquitous virus is causing AFM, Routh said.

“Enteroviruses circulate every year, so what is it about this certain very small group of people who rather than recovering from a mild viral virus go on to develop paralysis?” she wondered.

Uncovering the answer to that question will be pivotal to developing ways to prevent and treat AFM, according to Routh.

Prevention and treatment challenges

Experts are in the beginning stages of developing a vaccine against EV-D68, assuming that the virus causes AFM, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in an interview.

Janell Routh

“But when you have so few cases each year — as tragic as it is for the children who get it — it occurs in only one in a million people. When something occurs in one in a million people, it’s kind of tough to get a vaccine that would be deployable to anybody because you won’t know who to vaccinate,” Fauci said. “If AFM explodes in 2020 or 2022 into something much more prevalent like we saw with polio, then the issue of a vaccine will become much more relevant.”

PAGE BREAK

Currently, there is no vaccine for the viruses most often associated with AFM, so general infection prevention strategies, such as good hygiene, staying home when sick, covering the mouth when coughing and sneezing and washing hands regularly, can be helpful in keeping children safe, Messacar said.

In addition to vaccine development, researchers are creating therapeutics for AFM, Vogt said.

“However, one big challenge is that AFM is a clinical syndrome that seems to have many different pathways that contribute to it — it’s not just one enterovirus and it’s not even just enteroviruses,” he said. “There are many different ways that AFM can be triggered. So, if we make a therapy that targets one of these particular viruses, there will still be other viruses that wouldn’t be targeted by that therapy.”

So far, the main treatment available for children with AFM is aggressive physical and occupational therapy, according to Vogt.

“Rehabilitation may mitigate some of the effects of the paralytic syndrome,” Fauci said.

Vogt and colleagues are currently developing human monoclonal antibodies to treat infections from viruses associated with AFM. Vogt said therapeutics such as fluoxetine and IV immunoglobulin have shown promise in lab tests and mice but not in humans with AFM.

Researchers recently identified a unique biological signature of AFM in CSF that could potentially aid in early diagnosis and, thus, improve the use of targeted treatments.

Matthew R. Vogt

The research, which was presented at IDWeek 2019, used RNA sequencing to evaluate host responses in CSF samples and classify possible AFM causes, such as EV-D68, EV-A71, West Nile virus and Powassan virus. Twenty-one of 130 CSF samples demonstrated a specific AFM signature.

Protein targeting, viral transcription, viral gene expression and translation initiation pathways were the CSF factors that most precisely differentiated between EV-D68- and EV-A71-associated AFM.

The signature predicted viral links to AFM with more than 80% accuracy but is “fairly specialized,” so its use in a clinical setting is not likely yet, according to the researchers.

“Once we begin to understand more about the pathogenesis, we can then move forward to treatment and prevention strategies,” Routh said. “I’m really hoping that in the next year we will be able to speak more clearly and have more evidence to support treatment for this illness.”

What to look for

It is important that clinicians are aware of AFM and its distinctive clinical presentations, Messacar said.

“AFM is a rare disease, but at the same time, it’s an incredibly serious disease that shouldn’t be missed,” Routh said.

PAGE BREAK

Acute onset of limb weakness in an arm or leg or unexplained weakness in the muscles of the face or throat — particularly following a febrile illness — should raise concern that the underlying cause may be AFM, and any child presenting with these symptoms should undergo a diagnostic work-up for AFM, according to Messacar.

David Kimberlin

Clinicians should be especially aware of these signs during the late summer to early fall months in even-numbered years, Vogt noted, although AFM can occur at any time. Since there is no therapy to prevent the progression of AFM and the disease can progress quickly over just a day or two, early recognition and hospitalization is key to getting children the supportive care they need if paralysis becomes life-threatening and affects the muscles that control swallowing or breathing, he added.

“There is no therapy that prevents the progression of paralysis,” Vogt said. “The need for hospitalization is because of how rapidly AFM can progress and if severe, the patients will need supportive care.”

If AFM is suspected, clinicians should collaborate with neurologic and infectious diseases specialists to diagnose the patient, Routh noted.

“There have been many children in past outbreaks who have had a delayed diagnosis due to weakness being attributed to another cause like a musculoskeletal trauma or a nerve injury when really that was due to spinal cord inflammation due to AFM,” Messacar said. “Knowing that AFM is a possibility, and knowing the differences between just fatigue or myalgias that can occur with influenza compared with localized flaccid or hypotonic weakness, is important to differentiate AFM from other common fatigues that can happen with other viral illnesses.”

To confirm a diagnosis of AFM, limb weakness indicative of AFM should be assessed with a lumbar puncture and MRI of the brain and spine, he noted.

“Once a diagnosis of AFM is confirmed, clinicians should be looking for what could have triggered or caused the condition,” Messacar said.

Prompt collection of biologic specimens by swabbing the back of the nose and throat, and obtaining the spinal fluid, blood samples and stool samples is important to help advance the understanding of what is causing AFM and understand clinical phenotypes and prognosis associated with specific pathogens, according to Messacar.

‘On high alert’

In addition to the CDC and NIH, there is an AFM working group — “a self-organized collection of clinicians of all sorts” — working on trying to solve AFM, according to Vogt.

PAGE BREAK

“The United States is more prepared now for an outbreak of AFM than ever,” he said.

In the event that the U.S. experiences another surge of AFM cases in 2020, the CDC will immediately host a Clinician Outreach and Communications Activity (COCA) call to rapidly communicate urgent information to clinical providers, Routh said.

“We really are on high alert right now for a possibility of an outbreak in 2020, which we were not in past years because we weren’t even sure what we were dealing with,” Fauci said.

Although the U.S. is better equipped for another outbreak of AFM in 2020, AFM remains unique, and there is still much to learn about the disease, according to Routh. She said the NIH and the CDC are collaborating to study the natural history of the disease.

“This study will advance our understanding of the disease and create a biorepository that will promote additional AFM research in the future,” David Kimberlin, MD, an ex officio member of the AAP Committee on Infectious Diseases and principal investigator of the NIH study on AFM, told Infectious Diseases in Children.

Patients with limb weakness who are suspected of having AFM will be enrolled in the study and followed at regular intervals through the course of their hospitalization and up to a year after their hospitalization for follow-up, according to Routh.

The study will assess patients across a wide geographic region in the U.S. and other countries, including Canada, England and Peru, Vogt said. Members of the patients’ households who have been infected with the same viruses but did not get AFM will act as the controls in the study, he said.

“This study looks to be very key in helping us try to identify what factors influence why one patient gets AFM while everyone else in their family are only mildly affected with these respiratory illnesses,” Vogt said.

The study of the natural history of AFM will be the first opportunity to get standardized data on different treatment modalities for AFM and link those to outcomes, according to Routh.

“Right now, we don’t have an armamentarium of tools to be able to slow or stop the outbreak like we do with other diseases, such as measles,” she said. “The one thing that we really can do is target and improve patient care by letting clinicians know about AFM, know that we are seeing cases and put information out there so that they can easily recognize and hospitalize these patients. Our community does believe that with early access to care and intervention, we may be able to change outcomes for these children.” – by Alaina Tedesco

PAGE BREAK

Disclosures: Fauci, Messacar and Routh report no relevant financial disclosures. Kimberlin reports being the principal investigator of the NIH natural history study of AFM, which is funded through awards received by his university from the NIAID. Vogt reports being an inventor on a patent application for a human monoclonal antibody being developed as a potential therapeutic specifically for EV-D68.

Click here to read the Point/Counter "Are enteroviruses the predominant cause of AFM in the US?"