#14,212
Earlier this month, in CDC Vital Signs: Acute Flaccid Myelitis (AFM), we revisited the topic of Acute flaccid myelitis (AFM) - a rare illness that affects the nervous system - and is most commonly reported in small children.
While the exact causes of Acute flaccid myelitis aren't fully understood, it has been linked to a number of viral infections, including West Nile Virus, Adenoviruses, and a number of (polio and non-polio) enteroviruses, including EV-71 and more recently, EV-D68.Five years ago, in the early fall of 2014, we saw a nationwide outbreak of EV-D68 (49 states), producing a wide range of illness, including severe respiratory distress, resulting in the hospitalization of hundreds of children (see CDC HAN Advisory On EV-D68).
At the same time, doctors around the country reported a concurrent spike in polio-like paralysis in children (e.g. AFP or AFM (Acute Flaccid Myelitis)) often following a viral illness.Every two years since then (fall of 2016 and 2018) we've seen an increase in AFM cases (see at top of blog), with the largest wave (n=233) reported last fall. The CDC has confirmed 570 cases since they began tracking AFM in August of 2014.
The CDC's latest Investigation Update reads:
- Most of the patients with AFM (more than 90%) had a mild respiratory illness or fever consistent with a viral infection before they developed AFM.
- Viral infections such as from enteroviruses are common, especially in children, and most people recover. We don’t know why a small number of people develop AFM, while most others recover. We are continuing to investigate this.
- These AFM cases are not caused by poliovirus; all the stool specimens from AFM patients that we received tested negative for poliovirus.
- We detected coxsackievirus A16, EV-A71, and EV-D68 in the spinal fluid of four of 570 confirmed cases of AFM since 2014, which points to the cause of those patients’ AFM. For all other patients, no pathogen (germ) has been detected in their spinal fluid to confirm a cause.
- Most patients had onset of AFM between August and October, with increases in AFM cases every two years since 2014. At this same time of year, many viruses commonly circulate, including enteroviruses, and will be temporally associated with AFM.
- Most AFM cases are children (over 90%) and have occurred in 48 states and DC.
While the authors don't present a smoking gun, they do provide more evidence that elevated EV-D68 circulation is associated with spikes in AFM, and make a case for recent evolutionary changes in the virus making its more neuroinvasive.I've only included a few excerpts, so follow the link below to read it in its entirety. When you return, I'll have a brief postscript.
Volume 25, Number 9—September 2019
Research
Association of Enterovirus D68 with Acute Flaccid Myelitis, Philadelphia, Pennsylvania, USA, 2009–2018
Priyanka Uprety, Darcy Curtis, Michael Elkan, Jeffrey Fink, Ramakrishnan Rajagopalan, Chunyu Zhao, Kyle Bittinger, Stephanie Mitchell, Erlinda R. Ulloa, Sarah Hopkins, and Erin H. Graf
Abstract
Acute flaccid myelitis (AFM) is a polio-like disease that results in paralysis in previously healthy persons. Although the definitive cause of AFM remains unconfirmed, enterovirus D68 (EV-D68) is suspected based on 2014 data demonstrating an increase in AFM cases concomitant with an EV-D68 outbreak. We examined the prevalence in children and the molecular evolution of EV-D68 for 2009–2018 in Philadelphia, Pennsylvania, USA.
We detected widespread EV-D68 circulation in 2009, rare detections in 2010 and 2011, and then biennial circulation, only in even years, during 2012–2018. Prevalence of EV-D68 significantly correlated with AFM cases during this period. Finally, whole-genome sequencing revealed early detection of the B1 clade in 2009 and continued evolution of the B3 clade from 2016 to 2018. These data reinforce the need to improve surveillance programs for nonpolio enterovirus to identify possible AFM triggers and predict disease prevalence to better prepare for future outbreaks.(SNIP)
Although the definitive cause of AFM remains unknown, growing evidence (13,14) supports the association between EV-D68 and AFM. Epidemiologists have found that similar temporal associations between the 2014 EV-D68 outbreak and AFM cases also occurred in other countries (14). Hixon et al. found that paralysis could be elicited in mice infected with EV-D68 strains from the 2014 outbreak (15). As in children with AFM, these EV-D68–infected mice had a loss of motor neurons in the anterior horns of spinal cord segments corresponding to paralyzed limbs. Last, virus isolated from spinal cords of infected mice transmitted disease when injected into naive mice (15).
Despite the mounting evidence (13,14), the association between EV-D68 and AFM remains controversial. The detection of EV-D68 primarily in respiratory specimens with a concomitant lack of regular detection in cerebrospinal fluid (CSF) (7,16) continues to cast doubt, even though other neurotropic viruses (such as polioviruses) have similar detection patterns (14).
What remains to be shown for EV-D68 is whether its genome has changed over time to enable increased neurotropism. Since the first description of the nonneuroinvasive EV-D68 prototype in 1962, different genetic clades associated with neuroinvasion have been identified (15). Whole-genome sequencing (WGS) of the 2014 epidemic strains (dominated by clade B1) demonstrated a possible association between specific polymorphisms in EV-D68 and their overlap with other neurotropic and AFM-causing enteroviruses, such as poliovirus or enteroviruses D70 and A71 (16).
These data suggest that the EV-D68 genome has changed over time to enable neurotropism or possibly increased virulence resulting in more widespread disease. Given that most studies have been based based on partial instead of WGS, we also might be underestimating the number of clinically important genetic mutations in EV-D68 that drive increased infections with poor patient outcomes.
(SNIP)
The data presented here strengthen the association between EV-D68 infection and AFM. They also support the need for continued surveillance for EV-D68 in the United States and worldwide as the virus continues to circulate perhaps biennially, with unique prevalence in geographic pockets. Genomic analysis, particularly WGS, is also critical to clarify transmission, clade changes, and subsequent implications for immunity. WGS is also important for the association of specific genomic changes with the ability of the virus to cause AFM, requiring experimental analysis of mutations analogous to the extensive work done in poliovirus and enterovirus 71. Overall, these data reinforce the need to improve EV-D68 surveillance programs as a means of identifying possible AFM triggers that may lead the therapeutic interventions for this severe condition.
Dr. Uprety is a clinical microbiology postdoctoral fellow at the Perelman School of Medicine, University of Pennsylvania, and CHOP. Her primary research interests include applications of clinical metagenomics and molecular epidemiology.
The notion that EV-D68 has evolved into a more neurotropic virus is not new, and is something we looked at in some depth nine months ago in mBio: Contemporary EV-D68 Strains Have Acquired The Ability To Infect Human Neuronal Cells.
Using both mice and neuronal cell lines (SH-SY5Y cells), along with non-neuronal cell lines (HeLa & A549 cells), researchers demonstrated differences in viral entry and replication between older (clade A) EV-D68 strains, and newer (clade B1, B2, and D1) strains, which appear to have emerged early in the 21st century.Again, not definitive, but suggestive. And a reminder that viruses (and other pathogens) change over time - and what we observed and held to be true yesterday - may not hold true tomorrow.
