The Medical Thread

Opioid overdose deaths have led to a sharp increase in lifesaving organ transplants.

The night before Hatem Tolba received the liver transplant that saved his life, he lay comatose in a hospital intensive care unit. A dialysis machine was doing the work of his kidneys, and a cocktail of medications kept his heart beating.

Four years later, he has gained back 50 pounds, and his jaundiced eyes have cleared. Sitting in the dining room of the suburban house he shares with his wife and daughter in Shrewsbury, Massachusetts, the 49-year-old says his new liver is like having “a whole new engine.”

But Tolba’s remarkable recovery from liver failure has a painful undertone: He got a transplant because of a preventable tragedy. Though he knows few details about his donor, he was told the 21-year-old man died of an opioid overdose. And it weighs on him. “It’s kind of a quagmire, to be honest with you,” he says. “I can’t imagine a family losing a child in that way.”

While the number of opioid overdose deaths nationwide has doubled since 2008, the number of those victims who have become organ donors has quadrupled. Partially as a result of the newly available organs from overdose deaths, the list of people waiting for transplants — nearly 124,000 at its peak in 2014 — has begun to shrink for the first time, after 25 years of continuous growth.

Massachusetts, where Tolba lives, may be the epicenter of the convergence of these two crises. In 2016, nearly 2,000 residents of the state died of opioid overdoses, a rate 2.5 times the national average. Meanwhile that year, more than one-third of organ donors in the state died of drug overdoses, the highest share in the country.

That the overdose epidemic would have this silver lining was not a forgone conclusion. It’s only been possible due to the generosity of overdose victims and their families. Clinicians have also had to adopt new practices to make it possible. And patients who receive such transplants have had to accept additional risks — and are often left, like Tolba, grappling with challenging emotions about the toll that made their survival possible.

The infamous pesticide DDT has been further implicated as a possible trigger for the development of autism spectrum disorder by an international group of epidemiologists and psychiatrists studying children who were exposed in utero.

Their findings, now published in the American Journal of Psychiatry, present the first evidence of a link between the banned chlorine-based chemical and the neurological condition that was drawn from cases where the mother was confirmed to have DDT in her body – past research has relied on estimated exposures calculated by each woman’s residential proximity to DDT-polluted areas.

“DDT is still persisting in the environment and is detectable in almost everyone,” lead author Dr Alan Brown told IFL Science. “I would not say women should be concerned but it is important to be informed that at least this one chemical exposure is related to increased risk.”

DDT was first synthesized by chemists in 1874, but it wasn’t widely used until its insecticidal properties were discovered in 1939. For the next several decades, the compound was freely and generously sprayed on food crops worldwide and directly into public spaces and people’s homes.

But based on mounting evidence that the pesticide was harmful to both animals and humans, DDT was banned in the US in 1972 and in the European Union in 1986. In the time since, additional studies have confirmed that DDT accumulates and lingers in ecosystems, and that when ingested or inhaled, it can lead to reproductive issues and cancer.

Hoping to substantiate past work, Dr Brown’s group drew data from a large, nationwide Finnish study that took blood serum samples from women during more than 1 million pregnancies that occurred between 1987 and 2005. Subjects of the current investigation included 778 of the resulting non-twin children who had been diagnosed with autism at any time point up to 2007, as well as 778 control children who were each matched, one-to-one, to each subject with autism in regards to date of birth, place of birth, and place of residence.

The level of DDT in the mother’s system was quantified by a laboratory test for DDE, the chemical that DDT is metabolized into.

Examining this data revealed that the likelihood of autism was 32 percent higher in children whose mothers harbored DDE levels in the 75th percentile (of the range of concentrations in all subject’s mothers), after statistical adjustment for the influence of maternal age, family history of psychiatric disorders, number of siblings, and others. Furthermore, the odds of autism with intellectual disability were a staggering 121 percent higher if the mother had DDE levels above this threshold.

The study also looked at the risks associated with a class of industrial chemicals called polychlorinated biphenyls (PC Bs) that were banned in 1979 in the US and in 1985 in Europe, but no association with autism was found. Confusingly, a similarly designed 2016 study did find a link to PC Bs and failed to identify one with DDT.

Of course, DDT is not the only environmental toxin suspected to drive epigenetic changes during fetal development. Dr Brown hopes his group’s results will help clarify which chemicals to study further based on the developmental pathways they alter. Both DDT and PC Bs affect the actions of male sex hormones in utero – which are being increasingly implicated in autism – yet do so differently. DDT is known to inhibit the production and function of receptors for these hormones, whereas PC Bs increase the number of receptors.

As the summer of 2014 gave way to fall, Kevin Messacar, a pediatrician at Children’s Hospital Colorado, started seeing a wave of children with inexplicable paralysis. All of them shared the same story. One day, they had a cold. The next, they couldn’t move an arm or a leg. In some children, the paralysis was relatively mild, but others had to be supported with ventilators and feeding tubes after they stopped being able to breathe or swallow on their own.

The condition looked remarkably like polio—the viral disease that is on the verge of being eradicated worldwide. But none of the kids tested positive for poliovirus. Instead, their condition was given a new name: acute flaccid myelitis, or AFM. That year, 120 people, mostly young children, developed the condition across 34 states. The cases peaked in September and then rapidly tailed off.

“We didn’t know if it would go away,” Messacar says. “Unfortunately, it came back.”

After just a few dozen new cases the following year, AFM returned in force in 2016, afflicting 149 more people. The next year: another lull. And in 2018: another spike, with 62 confirmed cases so far and at least 93 more under investigation. Parents have described their children collapsing mid-run like “marionette dolls,” or going to bed with a fever and waking up paralyzed from the neck down.

This third wave confirms what many doctors had feared: AFM wasn’t a one-off, but likely a new biennial normal. It’s still rare, affecting just one in 1 million people, but that’s little comfort for the roughly 400 children who’ve been affected, many of whom are looking at lifelong disability or paralysis. “It’s exceptionally frustrating to see it again this year, when we know how much people’s lives are overturned,” says Priya Duggal from the Johns Hopkins Bloomberg School of Public Health. “We don’t really know much more than we knew in 2014—but we’re trying.”

AFM is a new term, but not a new syndrome. Its package of symptoms can be caused by a wide range of factors, including, as the Centers for Disease Control and Prevention notes, poliovirus, West Nile virus, environmental toxins, and genetic disorders. The question isn’t what causes AFM per se, but what is specifically behind the biennial spikes that have appeared since 2014. (There was a small peak in 2012, too, before the condition came to national attention.)

That has proven to be a tough problem to crack. In this era, it seems that scientists could easily grab tissue samples, sequence the genes of everything in them, and pinpoint some consistent microbial culprit. But that hasn’t happened—so far, no single germ has shown up in every case. Despite all the tools of modern science, new diseases, especially rare ones, can be very hard to understand.

AFM is uncommon enough that a hospital might get just a handful of cases in a given year, if any. Many centers must join forces to pull off a rigorous study—and that’s logistically complicated. The condition is also geographically unpredictable. Some places had cases in 2014 but none this year, and vice versa.

More importantly, it’s too risky to take biopsies of the actual affected tissues—the nerves of the brain and spine. Instead, doctors have mostly drawn and analyzed samples of spinal fluid, and there’s no guarantee that whatever causes AFM is actually there.

So far, most of the signs point toward a virus as the cause, and specifically some kind of enterovirus. Unlike influenza, which circulates in the winter, enteroviruses are infections of the autumn, which is when AFM cases peak. They mostly infect young children, and the average AFM patient is 4 years old. Enteroviruses need a large enough population of susceptible hosts in which to circulate, so many lie low after waves of infection and crop up in cycles of two or three years—just as AFM does. And although many enteroviruses circulate widely but have little effect, they have a track record of occasionally infecting the spinal cord and causing paralytic illnesses.

“It’s not too far of a jump” to suspect them, says Roberta De Biasi, an infectious-disease chief at Children’s National Health System.

One particular enterovirus, known as EV-D68, has emerged as the lead suspect. First discovered in 1962, it seemed rare and unexceptional. But in 2014, it caused a huge surge of respiratory illness throughout the United States. That year, “our hospital was the busiest it’s ever been,” Messacar recalls. “The floors were packed, and we hit capacity.” And when paralyzed children started showing up at the same time, he put two and two together. He and others noted that in 2014 and 2016, EV-D68 was the most commonly identified virus in people with AFM.

But it’s not in every patient. So far, the CDC has only found the virus in the spinal fluid of a single child, and in fewer than half of the stool samples or nasal swabs it tested. “I am frustrated that, despite all of our efforts, we haven’t been able to identify the cause of this mystery illness,” said Nancy Messonnier, who directs the CDC’s National Center for Immunization and Respiratory Diseases, in a recent press briefing. The agency notes on its website that “the cause of most of the AFM cases remains unknown.”

Messacar thinks the case for EV-D68 is stronger than the CDC is admitting. Certainly, caution is commendable; the wrong viruses have been blamed for perplexing illnesses before. But “I don’t think AFM is as much of an unknown as it’s portrayed,” he says. He is frustrated with its billing as a “mystery illness.”

Enteroviruses, he says, are not like typical nerve-infecting germs. They can move through nerves directly, so they don’t always show up in spinal fluid. And EV-D68 isn’t even like typical enteroviruses. Unlike other members of its family, it is quickly destroyed in the gut, and doesn’t show up in stool. It mostly thrives at the back of the nose—a place that few doctors thought to examine when AFM first showed up. Why look inside the respiratory tract of a child with a neurological disease?

Even when doctors did take nasal swabs, their odds of finding EV-D68 were low. In many neurological infections, the worst symptoms aren’t caused by the virus itself, but by the body’s disproportionate immune response. That response can continue even after the virus has been cleared, which means that patients often test negative for whatever first triggered their illness. All the researchers I spoke to think AFM likely behaves in this way, especially since there can be a seven-day gap between the condition’s initial coldlike symptoms and the severe paralytic ones. By the time parents seek medical help, their children could be suffering from their body’s misplaced attempts to fight an enemy that’s no longer there. “The expectation that you’ll find a pathogen in every case is unrealistic because you’re already behind the clock,” Messacar says.

As a work-around, researchers could take the complicated step of analyzing the bodily fluids of AFM patients for immune cells or antibodies that specifically recognize EV-D68. Their existence would at least suggest that the virus was once present. But even without such confirmation, there are other lines of incriminating evidence.

After the EV-D68 epidemic of 2014, a few hospitals, including Messacar’s, started actively searching for the virus in nasal swabs taken from patients with generic cold symptoms. Their surveillance showed that the virus disappeared in 2015 and returned a year later, coinciding with the second AFM wave. It vanished again in 2017 and returned this summer. When the latest AFM wave hit, Children’s Hospital Colorado actually saw it coming.

There’s also compelling evidence from laboratory studies. Last year, Alison Hixon at the University of Colorado School of Medicine showed that EV-D68 strains from the 2014 outbreak can paralyze mice by infecting and killing the movement-controlling neurons in their spine. When Hixon isolated the virus from those neurons and injected it into another group of mice, those rodents also became paralyzed. That fulfills all the traditional criteria for causality. It falls short of a slam-dunk case only because the experiments were done in mice.

Another enterovirus, EV-71, has also been implicated in AFM. It’s endemic to East Asia, where it infrequently causes a similar polio-like illness with the same two-to-three-year periodicity. Messacar’s team detected it in Colorado this spring, and they’ve found it in 11 patients with AFM. Several enteroviruses could be behind the AFM cases.

But even if that’s true, it doesn’t explain why the disease suddenly became a national problem in 2014. Conspiratorial corners of the internet were quick to suggest that immigrants had imported a mystery virus—a ludicrous hypothesis, since EV-D68 was first identified in California five decades ago.

It’s possible, though, that the virus has changed since then. In one experiment, strains from 1962 didn’t paralyze mice in the same way that those from 2014 did. This would hardly be the first time that long-known viruses suddenly became more dangerous. Zika virus, for example, was thought to be innocuous when it was discovered in the 1940s, but only recently acquired a mutation that seemingly allows it to cause severe neurological problems.

“For me, it’s not really about the viruses,” Duggal, from Johns Hopkins, says. “I’m really trying to figure out what causes the paralysis.” Much like poliovirus, which paralyzed just 1 percent of those it infected, it’s likely that AFM is caused by widely circulating viruses that only lead to problems for a small, susceptible minority. That’s why you don’t hear news reports of entire schools coming down with AFM. The disease doesn’t even sweep through entire families: Whenever an affected child has had a sibling, Duggal says, that other child has always been healthy. In one dramatic case, scientists isolated genetically identical strains of EV-D68 from two California siblings, one of whom had AFM and the other of whom had the sniffles.

Duggal is now sequencing the genes of people from 60 affected families to see if the ones with AFM have any unique mutations. Other factors might be relevant, too. Gut bacteria, for example, can affect an animal’s susceptibility to polio. And since humidity and temperature affect the global circulation of enteroviruses, Carlos Pardo-Villamizar from the Johns Hopkins School of Medicine wonders if the world’s changing climate is influencing the new trends in AFM.

To an extent, every disease behaves like this. No germ sickens every person it infects. Instead, the outcomes of encounters between pathogens and hosts almost always depend on their respective genes and other factors like climate, diet, the microbiome, and more.

The point is: Diseases are complicated. If anything, scientists have been lucky to study many viruses—flu, Ebola, and smallpox, to name a few—that are potent enough for their consequences to be clear, regardless of other variables. But there’ll be many instances in which the threads of cause and effect are harder to untangle. Epstein-Barr virus, for example, infects half of Americans before they get to middle school, and 90 percent of them by adulthood. It usually does nothing, sometimes leads to mono, and very infrequently causes cancers.

AFM is similar, and its emergence provides a new opportunity for researchers to confront age-old questions. How do you prove what causes a disease? When does your evidence become strong enough? And while you’re collecting that evidence, what do you do for the people who are affected?

“In 2014 and 2016, there were only one or two cases of full recovery,” Duggal says. This year, for whatever reason, the children in Colorado infected with EV-71 are recovering more quickly. But at least one child has died, and some are facing long-term disabilities. Every patient immediately gets intensive physical therapy. If that fails, doctors have tried antibody infusions and plasmapheresis (a process that filters blood) to reduce inflammation, but it’s unclear if these do any good. “There’s no proven efficacy, but also little risk,” De Biasi, the infectious-disease chief, says. “Once you get to other therapies, you’re starting to go up the risk equation. It’s not a cookbook approach.”

There’s no clear line on prevention, either. With uncertainty lingering around viral causes, the CDC’s advice is generic: “It’s always important to practice disease prevention steps, such as staying up-to-date on vaccines, washing your hands, and protecting yourself from mosquito bites.” Basically: Do the stuff that prevents other diseases.

Messacar would like it to be bolder. By all means, he says, be open to changing evidence and continue looking at other possible causes, but in the meantime, proceed as if EV-D68 is the actual culprit. That means two things. First, begin developing vaccines, a process that could take years. “It may seem early to start thinking about that, but if we don’t do the groundwork and AFM comes back in a bigger way, we’re going to be years behind,” he says.

Second, Messacar says, public-health workers should actively search for the virus in the same way they do for the flu. The CDC does have a surveillance program for enteroviruses, but it’s a passive system that relies on clinicians sending in samples. A more active program, of the kind that only a few hospitals do, would specifically test for EV-D68 in the nose of any child who gets admitted with respiratory problems.

A month ago, after the third wave of AFM had started, Pardo-Villamizar began convening a nationwide group of colleagues from hospitals that were seeing cases. Their goal is to share as much information as possible on how best to study, diagnose, and treat the illness. “We always depend on the CDC, but they’re designed to establish surveillance for diseases, not management and diagnosis,” he says. “We, as clinicians and scientists, should be doing that.”

For Messacar, the most important step is to take the disease seriously. “Right now, it’s very uncommon compared to polio in the 1950s, which caused tens of thousands of cases a year,” he says. “But I don’t want to downplay this as a rare disease, because of the long-term consequences. It’s jumping up the list of public-health priorities, and it deserves increased funding and attention.” A fourth wave is likely to hit in 2020. He wants the country to be ready.