Acute Flaccid Myelitis in the United States: 2015–2017

Discussion

In our summary of national AFM surveillance from 2015 to 2017, we demonstrate that cases were widely distributed across the United States, the majority of cases occurred in late summer or fall, children were predominantly affected, there is a spectrum of clinical severity, and no single pathogen was identified as the primary cause of AFM. We conclude that symptoms of a viral syndrome within the week before limb weakness, detection of viral pathogens from sterile and nonsterile sites from almost half of patients, and seasonality of AFM incidence, particularly during the 2016 peak year, strongly suggest a viral etiology, including EVs.

EVs, such as poliovirus and EV-A71, can cause a wide clinical spectrum ranging from asymptomatic infection to much rarer presentations, such as multisystem organ failure and neuroinvasive disease (eg, limb paralysis and meningitis).^15–17 In 2014, multiple reports of AFM cases and concurrent outbreaks of severe respiratory disease caused by EV-D68 nationwide supported a temporal association between EV-D68 and AFM. Similar to other neuroinvasive EVs, EV-D68 can readily induce flaccid paralysis in mouse models and has been detected in CSF specimens of patients with AFM, albeit rarely.^18–26 In 2014, EV-D68 was the most common virus detected, accounting for 20% of respiratory specimens tested. However, multiple testing strategies (including virus-specific PCR or RT-PCR, broad “family-specific” PCR or RT-PCR, and metagenomic sequencing) did not identify a convincing single etiologic signal in sterile-site specimens.⁸

EV testing from 2015 through 2017 demonstrated similar findings to the 2014 investigation. Diagnostic yield from CSF was low (CV-A16 was detected in one patient in 2015, and EV-D68 was detected in one patient in 2014), multiple pathogens were identified from both sterile and nonsterile sites in approximately half of patients, and poliovirus was not detected in any cases. EV-D68 positivity from respiratory specimens of AFM patients with onset in 2015 to 2017 (24%) was similar to 2014; however, EV-D68 was also detected in patients later classified as noncases in this study. After the 2014 investigation, testing for EV-D68 increased because of wider availability of an EV-D68–specific assay, which allowed for more-rapid detection at treating facilities but still limited broader characterization of other type-specific EV circulation that could also be contributing to respiratory and neuroinvasive disease within a community.^27–29 Subnational estimates of EV-D68 circulation in the same regions where AFM cases are occurring have not been well characterized, although studies to evaluate these trends are being implemented. Although a temporal association between EV-D68 and AFM has been reported, additional evidence is still needed to more clearly establish a causal association.

EV circulation is widespread, with a US seasonal peak in the late summer and early fall²¹ complicating interpretations correlating EV-positive specimens from nonsterile sites with rare clinical outcomes like paralysis. Seroprevalence estimates of neutralizing antibodies for EVs range from 33% to 99%, depending on serotype.³⁰ The large burden of EV-D68 respiratory disease detected in 2014 led to hypotheses that EV-D68 was a newly emerging EV also associated with AFM. In a 2012 study of 436 subjects aged 2 to 81 years from Kansas City, Missouri, with sera collected before the 2014 EV-D68 respiratory outbreak, researchers demonstrated detection of neutralizing antibodies against the major 2014 EV-D68 outbreak strain for all subjects.³¹ Serologic evidence of widespread infection with EV-D68, even before the first notable increase of AFM in 2014, suggests that if EV-D68 was the primary cause of AFM in 2014 and 2016, other factors must play a role in the development of this rare outcome.

Because of limited availability of spinal pathology specimens, it remains unknown whether paralysis associated with AFM results from direct pathogen invasion of the central nervous system or a postinfectious process, possibly immune mediated. AFM may be analogous to other diseases that present as AFP, such as transverse myelitis or GBS, which are linked to immune-mediated damage of the spinal cord or peripheral nerves, respectively.^32,33 Alternatively, it may be similar to other EV pathogenesis, like poliovirus, which causes paralysis by direct viral destruction of motor neurons in the anterior horn of the spinal cord. EV-A71 has also been shown to cause brainstem encephalitis and paralysis via direct mechanisms.² The short interval between a preceding viral syndrome and onset of limb weakness in these AFM cases could support direct viral invasion as a mechanism. However, given that identification of a pathogen in the CSF is rare, further research into potential immunologic and genetic mechanisms leading to AFM, as well as more sophisticated pathogen evaluations, is warranted. Examinations of soluble and cell-associated markers of immune system activation, particularly in the central nervous system, are underway, as well as investigations of the potential role of other immune-mediated pathogeneses.

Globally, countries vary widely in their surveillance for acute flaccid limb weakness. Many countries conduct AFP surveillance to rule out poliovirus, a critical component of the poliovirus eradication initiative. Some countries, including France, Sweden, and the Netherlands, identify AFM cases through laboratory-based EV surveillance networks, which limits reporting of AFM cases caused by other potential pathogens.^34–38 In our data, viruses other than EVs were identified in 60% of patients with pathogens detected from a sterile site. Important differences in AFM case ascertainment make it challenging to compare the global epidemiology of AFM across countries.

There are several limitations to this analysis, including reliance on voluntary reporting from clinicians and state and local health departments. Although AFM is not a nationally notifiable condition, all states have either made AFM reportable or have reporting requirements for AFP without an alternate diagnosis or for new or emerging conditions of public health importance.. Variability in awareness can lead to underreporting to the health department and affect timely collection of appropriate specimens. Although the case definition was expanded in 2015 to include persons of all ages, adults may also have other reasons for weakness (eg, spinal cord stroke, GBS), making diagnosis of AFM more challenging in this population. AFM likely has a range of clinical severity, and only moderate or severe cases may present for clinical evaluation. Ongoing analysis of the spectrum of illness is necessary to inform surveillance methods and improve specificity and sensitivity of the current case definition. Lastly, EV surveillance to characterize type-specific annual trends and geographic variability is limited, challenging our ability to attribute one specific EV as the etiologic cause of AFM.