Defying forecasts that 2020 would see the highest spike yet in cases of acute flaccid myelitis (AFM), the confirmed case count through October is, in fact, the lowest since 2015, according to the Centers for Disease Control and Prevention (CDC).
After starting the year as predicted, with more confirmed cases than ever before in January, February, and March, the following seven months have seen the lowest total since the CDC began tracking the polio-like illness in 2014. The cliff drop since March has been especially striking because winter is the slow season for AFM, while August through October have been the peak months.
Neurologists and others who have been tracking AFM attribute the unexpected decline to the COVID-19 lockdowns, which are believed to be slowing the spread of enterovirus D68, the virus that causes most cases of AFM, even more effectively than that of SARS-CoV-2.
That silver lining to the pandemic, however, may be followed by more dark clouds, they said, in the form of a rebound once COVID-19 precautions fade and EV-D68 begins spreading again.
“The working theory is that the measures put in place for SARS-Cov2 seem to be having the same effect on enterovirus D68 and, therefore, on AFM," said Kevin Messacar, MD, a pediatric neurologist at the University of Colorado and member of the CDC's AFM Task Force. “I think we have basically distanced away enterovirus D68 from the large outbreak expected this year, which leaves the question for what will happen next year or the year after."
The preprint of a paper posted on medRxiv in July by Dr. Messacar and others offered an ominous forecast for how the COVID-19 lockdowns might ultimately increase the number of people, particularly children, who could develop AFM due to infection with EV-D68. “If social distancing prevents the outbreak [in 2020] from occurring," the paper states, “the susceptible pool may increase even further."
Even so, the delay is giving two teams of researchers more time to prepare if a large outbreak of AFM does eventually occur. In the Netherlands, a vaccine-development company announced on September 8 that it has been awarded a $9.4 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) to develop a vaccine against EV-D68.
US researchers, meanwhile, are seeking funding for a clinical trial of human monoclonal antibodies previously shown to thwart the development of AFM in mice.
“Any delay in an outbreak of AFM is a good thing—it gives us additional time to develop therapies and preventative measures," Dr. Messacar said.
Peaks and Troughs
Beginning with 120 cases in 2014, AFM has peaked in the United States every two years in the months from August to November, with each successive peak and trough higher than the last. After a lull in 2015, when just 24 cases were confirmed by the CDC, a second peak came in 2016, with 153. Another trough, of 38 cases, occurred in 2017, followed by a third peak in 2018, with 240.
Following last year's lull of 55 cases, the pattern looked strong enough to prompt the CDC to issue a press alert this August. The CDC “anticipates that 2020 will be another peak year," the release stated, and it encouraged parents, pediatricians, and neurologists to be on the lookout for the paralyzing condition.
Based on an analysis of the 2018 outbreak, the CDC reported: "In addition to weakness, common symptoms at clinical evaluation were gait difficulty (52 percent), neck or back pain (47 percent), fever (35 percent), and limb pain (34 percent)."
The report also noted that the median age of confirmed patients was 5.3 years. All but 2 percent of patients were hospitalized, the analysis found, while 54 percent were admitted to an intensive care unit, and one in four required mechanical ventilation. Yet hospitalization was delayed for two or three days after the onset of limb weakness in 25 percent of patients, and four or more days in 10 percent.
CNN, The New York Times, and Time magazine all published articles on the CDC's warning. But instead of a peak, as of October 30, the CDC has confirmed only two cases of AFM in August of this year (compared to 30 in 2018), one in September (compared to 88 in 2018), and zero in October (compared to 66 in 2018).
“I'm hoping there's not a boy-who-cried-wolf phenomenon," said Dr. Messacar. “I don't think that will be the case. I'm glad to have seen more education and awareness around a virus that can have devastating lifelong consequences."
Although the CDC long maintained an equivocal position as to the cause of AFM, its position has evolved with the accumulation of scientific papers pointing the finger at EV-D68. In its August press release, for instance, the CDC stated: “Enteroviruses, particularly enterovirus-D68...are likely responsible for these peaks in cases."
“I would say that CDC has always considered EV-D68 to be a potential cause of those every-other-year outbreaks," said Janell Routh, MD, MHS, medical officer and lead of the CDC's AFM and Domestic Poliovirus Team. “With recent evidence, we have definitely gained more information to support the relationship."
Dr. Routh pointed to a paper published a year ago in Nature Medicine, led by Michael Wilson, MD, associate professor of neurology at the University of California, San Francisco, reporting antibodies to enteroviruses in the spinal fluid of nearly 70 percent of AFM patients vs. fewer than 7 percent of controls.
A possible answer as to why outbreaks of EV-D68 have been coming in biannual waves was offered two years ago in a paper in Science led by Margarita Pons-Salort of the department of infectious disease epidemiology at Imperial College London. In fact, the paper showed, nearly all human enteroviruses come in remarkably regular waves. Using 15 years of surveillance data from Japan, she found that acquired serotype-specific immunity explains most of the patterns. According to her model, as a particular serotype spreads through a community, growing exposure results in growing immunity until the serotype stops spreading. This then results in a growing pool of immunologically susceptible individuals, especially newborns, and so the cycle begins again.
Prepping for Possible Rebound
The recent paper coauthored by Dr. Messacar and posted on medRxiv uses similar epidemiological modeling to conclude that the collapse in cases of AFM since lockdowns began in the spring will result in growing susceptibility and could, eventually, cause an outbreak even larger than the one previously predicted for this year. But he concedes that the extraordinary nature of the lockdowns, unlike anything seen since the Spanish flu pandemic of 1918-19, makes any such predictions uncertain.
“This is a never-before-done natural experiment that's happening right now," Dr. Messacar said. “We have basically social-distanced away all respiratory viruses except for COVID-19 during the strict lockdown. We're really in uncharted waters."
Benjamin M. Greenberg, MD, FAAN, professor of neurology at the University of Texas Southwestern Medical Center, said he too is unsure how seriously to assess the models predicting a rebound of EV-D68 and, with it, AFM.
“The models from viral ecologists, who do some amazing work on how you predict and track outbreaks, say that the every-other-year pattern has to do with how much immunity to the virus exists," Dr. Greenberg said. “In theory, as we prevent exposure and prevent cases, as we're doing now, we're going to increase the at-risk population for two years down the road. But nobody knows for certain. I'm willing to start the office pool now to see where we'll be in two years."
Despite the uncertainty, preparations continue for the development of medicines to prevent or treat AFM. The NIAID grant for an inactivated EV-D68 vaccine went to Intravacc, a Netherlands institute that specializes in making and testing vaccines. The $9.4 million should enable the firm to select a vaccine candidate and conduct a first-in-human Phase 1 trial.
Monoclonal antibodies against EV-D68 were shown in a study published in Science Immunology in July to prevent the development of AFM in a mouse model. But the senior author of the paper said that progress toward a human clinical trial has been slow.
“We're in what is often called the 'Valley of Death' in the biotech industry," said James E. Crowe, Jr., MD, director of the Vanderbilt Vaccine Center and professor of pediatrics and pathology, microbiology and immunology.
“We have antibodies that work very impressively in the mouse. The question is who's willing to put $10 million to $15 million to fund a phase 1 trial. Despite the fact that it's a very scary disease and it's terrible if your kid gets it, the frequency is not high enough that it's getting enough attention."
Two companies—ZabBio, which previously developed monoclonal antibodies against Ebola, and ID Biologics, a firm founded by Dr. Crowe—have received small grants from the National Institutes of Health keep their research into EV-D68 antibodies going.
“We were pushing very hard last year to get our antibody ready for this season," Dr. Crowe said. “We just did not have the wherewithal."
While relieved that the social distancing aimed at stopping the COVID-19 pandemic has brought a side benefit of preventing the spread of EV-D68, “That's only made the community of virologists more nervous," Dr. Crowe said. “If we skip a year, we might be storing up even more susceptible individuals. It could be like the California forest fires. If you don't burn the underbrush every two years, the tinder just keeps accumulating."
Disclosures: Drs. Messacar, Routhe, and Greenberg have no relevant disclosures.
Link Up for More Information
Park SW, Farrar J, Messacar K, et al. Epidemiological dynamics of enterovirus D68 in the US: implications for acute flaccid myelitis. Medrxiv. Posted July 23 2020.
Meyers L, Bard JD, Galvin B, et al. Enterovirus D68 outbreak detection through a syndromic disease epidemiology network. J Clin Virol 2020;124:104262.
