Why Neglected Tropical Diseases Should Matter to Americans
Daisy Hernández was five years old when one of her favorite aunts was struck with a mysterious illness. Tía Dora had stayed behind in Colombia when Daisy's mother immigrated to Union City, New Jersey. A schoolteacher in her late 20s, she began suffering from fevers and abdominal pain, and her belly grew so big that people thought she was pregnant. Exploratory surgery revealed that her large intestine had swollen to ten times its normal size, and she was fitted with a colostomy bag. Doctors couldn't identify the underlying problem—but whatever it was, they said, it would likely kill her within a year or two.
Tía Dora's sisters in New Jersey—Hernández's mother and two other aunts—weren't about to let that happen. They pooled their savings and flew her to New York City, where a doctor at Columbia-Presbyterian Medical Center with a penchant for obscure ailments provided a diagnosis: Chagas disease. Transmitted by the bite of triatomine insects, commonly known as kissing bugs, Chagas is endemic in many parts of Latin America. It's caused by the parasite Trypanoma cruzi, which usually settles in the heart, where it feeds on muscle tissue. In some cases, however, it attacks the intestines or esophagus. Tía Dora belonged to that minority.
In 1980, U.S. immigration laws were more forgiving than they are today. Tía Dora was able to have surgery to remove a part of her colon, despite not being a citizen or having a green card. She eventually married a legal resident and began teaching Spanish at an elementary school. Over the next three decades, she earned a graduate degree, built a career, and was widowed. Meanwhile, Chagas continued its slow devastation. "Every couple of years, we were back in the hospital with her," Hernández recalls. "When I was in high school, she started feeling like she couldn't swallow anything. It was the parasite, destroying the muscles of her esophagus."
When Tía Dora died in 2010, at 59, her niece was among the family members at her bedside. By then, Hernández had become a journalist and fiction writer. Researching a short story about Chagas disease, she discovered that it affected an estimated 6 million people in South America, Central America, and Mexico—as well as 300,000 in the United States, most of whom were immigrants from those places. "I was shocked to learn it wasn't rare," she says. "That made me hungry to know more about this disease, and about the families grappling with it."
Hernández's curiosity led her to write The Kissing Bug, a lyrical hybrid of memoir and science reporting that was published in June. It also led her to another revelation: Chagas is not unique. It's among the many maladies that global health experts refer to as neglected tropical diseases—often-disabling illnesses that afflict 1.7 billion people worldwide, while getting notably less attention than the "big three" of HIV/AIDs, malaria, and tuberculosis. NTDs cause fewer deaths than those plagues, but they wreak untold suffering and economic loss.
Shortly before Hernández's book hit the shelves, the World Health Organization released its 2021-2030 roadmap for fighting NTDs. The plan sets targets for controlling, eliminating, or eradicating all the diseases on the WHO's list, through measures ranging from developing vaccines to improving healthcare infrastructure, sanitation, and access to clean water. Experts agree that for the campaign to succeed, leadership from wealthy nations—particularly the United States—is essential. But given the inward turn of many such countries in recent years (evidenced in movements ranging from America First to Brexit), and the continuing urgency of the COVID-19 crisis, public support is far from guaranteed.
As Hernández writes: "It is easier to forget a disease that cannot be seen." NTDs primarily affect residents of distant lands. They kill only 80,000 people a year, down from 204,000 in 1990. So why should Americans to bother to look?
Breaking the circle of poverty and disease
The World Health Organization counts 20 diseases as NTDs. Along with Chagas, they include dengue and chikungunya, which cause high fevers and agonizing pain; elephantiasis, which deforms victims' limbs and genitals; onchocerciasis, which causes blindness; schistosomiasis, which can damage the heart, lungs, brain, and genitourinary system; helminths such as roundworm and whipworm, which cause anemia, stunted growth, and cognitive disabilities; and a dozen more. Such ailments often co-occur in the same patient, exacerbating each other's effects and those of illnesses such as malaria.
NTDs may be spread by insects, animals, soil, or tainted water; they may be parasitic, bacterial, viral, or—in the case of snakebite envenoming—non-infectious. What they have in common is their longtime neglect by public health agencies and philanthropies. In part, this reflects their typically low mortality rates. But the biggest factor is undoubtedly their disempowered patient populations.
"These diseases occur in the setting of poverty, and they cause poverty, because of their chronic and debilitating effects," observes Peter Hotez, dean of the National School of Tropical Medicine at Baylor University and co-director of the Texas Children's Hospital for Vaccine Development. And historically, the everyday miseries of impoverished people have seldom been a priority for those who set the global health agenda.
That began to change about 20 years ago, when Hotez and others developed the conceptual framework for NTDs and early proposals for combating them. The WHO released its first roadmap in 2012, targeting 17 NTDs for control, elimination, or eradication by 2020. (Rabies, snakebite, and dengue were added later.) Since then, the number of people at risk for NTDs has fallen by 600 million, and 42 countries have eliminated at least one such disease. Cases of dracunculiasis—known as Guinea worm disease, for the parasite that creates painful blisters in a patient's skin—have dropped from the millions to just 27 in 2020.
Yet the battle is not over, and the COVID-19 pandemic has disrupted prevention and treatment programs around the globe.
A new direction — and longstanding obstacles
The WHO's new roadmap sets even more ambitious goals for 2030. Among them: reducing by 90 percent the number of people requiring treatment for NTDs; eliminating at least one NTD in another 100 countries; and fully eradicating dracunculiasis and yaws, a disfiguring skin infection.
The plan also places an increased focus on "country ownership," relying on nations with high incidence of NTDs to design their own plans based on local expertise. "I was so excited to see that," says Kristina Talbert-Slagle, director of the Yale College Global Health Studies program. "No one is a better expert on how to address these situations than the people who deal with it day by day."
Another fresh approach is what the roadmap calls "cross-cutting" targets. "One of the really cool things about the plan is how much it emphasizes coordination among different sectors of the health system," says Claire Standley, a faculty member at Georgetown University's Center for Global Health Science and Security. "For example, it explicitly takes into account the zoonotic nature of many neglected tropical diseases—the fact that we have to think about animal health as well as human health when we tackle NTDs."
Whether this grand vision can be realized, however, will depend largely on funding—and that, in turn, is a question of political will in the countries most able to provide it. On the upside, the U.S. has ended its Trump-era feud with the WHO. "One thing that's been really encouraging," says Standley, "has been the strong commitment toward global cooperation from the current administration." Even under the previous president, the U.S. remained the single largest contributor to the global health kitty, spending over $100 million annually on NTDs—six times the figure in 2006, when such financing started.
On the downside, America's outlay has remained flat for several years, and the Biden administration has so far not moved to increase it. A "back-of-the-envelope calculation," says Hotez, suggests that the current level of aid could buy medications for the most common NTDs for about 200 million people a year. But the number of people who need treatment, he notes, is at least 750 million.
Up to now, the United Kingdom—long the world's second-most generous health aid donor—has taken up a large portion of the slack. But the UK last month announced deep cuts in its portfolio, eliminating 102 previously supported countries and leaving only 34. "That really concerns me," Hotez says.
The struggle for funds, he notes, is always harder for projects involving NTDs than for those aimed at higher-profile diseases. His lab, which he co-directs with microbiologist Maria Elena Bottazzi, started developing a COVID-19 vaccine soon after the pandemic struck, for example, and is now in Phase 3 trials. The team has been working on vaccines for Chagas, hookworm, and schistosomiasis for much longer, but trials for those potential game-changers lag behind. "We struggle to get the level of resources needed to move quickly," Hotez explains.
Two million reasons to care
One way to prompt a government to open its pocketbook is for voters to clamor for action. A longtime challenge with NTDs, however, has been getting people outside the hardest-hit countries to pay attention.
The reasons to care, global health experts argue, go beyond compassion. "When we have high NTD burden," says Talbert-Slagle, "it can prevent economic growth, prevent innovation, lead to more political instability." That, in turn, can lead to wars and mass migration, affecting economic and political events far beyond an affected country's borders.
Like Hernández's aunt Dora, many people driven out of NTD-wracked regions wind up living elsewhere. And that points to another reason to care about these diseases: Some of your neighbors might have them. In the U.S., up to 14 million people suffer from neglected parasitic infections—including 70,000 with Chagas in California alone.
When Hernández was researching The Kissing Bug, she worried that such statistics would provide ammunition to racists and xenophobes who claim that immigrants "bring disease" or exploit overburdened healthcare systems. (This may help explain some of the stigma around NTDs, which led Tía Dora to hide her condition from most people outside her family.) But as the book makes clear, these infections know no borders; they flourish wherever large numbers of people lack access to resources that most residents of rich countries take for granted.
Indeed, far from gaming U.S. healthcare systems, millions of low-income immigrants can't access them—or must wait until they're sick enough to go to an emergency room. Since Congress changed the rules in 1996, green card holders have to wait five years before they can enroll in Medicaid. Undocumented immigrants can never qualify.
Closing the great divide
Hernández uses a phrase borrowed from global health crusader Paul Farmer to describe this access gap: "the great epi divide." On one side, she explains, "people will die from cancer, from diabetes, from chronic illnesses later in life. On the other side of the epidemiological divide, people are dying because they can't get to the doctor, or they can't get medication. They don't have a hospital anywhere near them. When I read Dr. Farmer's work, I realized how much that applied to neglected diseases as well."
When it comes to Chagas disease, she says, the epi divide is embodied in the lack of a federal mandate for prenatal or newborn screening. Each year, according to the Centers for Disease Control and Prevention, up to 300 babies in the U.S. are born with Chagas, which can be passed from the mother in utero. The disease can be cured with medication if treated in infancy. (It can also be cured in adults in the acute stage, but is seldom detected in time.) Yet the CDC does not require screening for Chagas—even though newborns are tested for 15 diseases that are less common. According to one study, it would be 10 times cheaper to screen and treat babies and their mothers than to cover the costs related to the illness in later years. Few states make the effort.
The gap that enables NTDs to persist, Hernández argues, is the same one that has led to COVID-19 death rates in Black and Latinx communities that are double those elsewhere in America. To close it, she suggests, caring is not enough.
"When I was working on my book," she says, "I thought about HIV in the '80s, when it had so much stigma that no one wanted to talk about it. Then activists stepped up and changed the conversation. I thought a lot about breast cancer, which was stigmatized for years, until people stepped forward and started speaking out. I thought about Lyme disease. And it wasn't only patients—it was also allies, right? The same thing needs to happen with neglected diseases around the world. Allies need to step up and make demands on policymakers. We need to make some noise."
Drugs That Trick Older People’s Bodies to Behave Younger Might Boost the Effectiveness of a COVID-19 Vaccine
In our April 23rd editorial for this magazine, we argued that addressing the COVID-19 pandemic requires that we both fight the SARS-CoV-2 virus and fortify the human hosts who are most vulnerable to it.
Two recent phase 2 studies in older adults have suggested that a new category of drugs called rapalogues can in some cases increase the immunization capacity of older adults.
Because people over 70 account for more than 80 percent of reported COVID-19 deaths globally, this means we must do everything possible to protect our elders.
A range of recent studies have suggested that systemic knobs might metaphorically be turned to slow the cellular aging process, making us better able to fight off the many diseases correlated with aging. These types of systemic changes might be used to stem the specific decline in immunity caused by aging and to increases the biological capacity of elderly people to effectively fight viral infection.
But while helping make older people more resilient in the face of a viral infection is critical, that's not the only way geroscience can help in our fight against this deadly pandemic.
As we move toward hopefully developing one or more COVID-19 vaccines, researchers must more fully appreciate the ways in which traditional vaccines can be less effective in older people than in younger ones.
Repeated studies have shown that the flu vaccine, for example, has lower efficacy in older people than in younger ones. Older people tend to develop fewer antibodies after being vaccinated because a subset of their white blood cells, called T cells, have become less responsive over time. Some inflammatory peptides that increase with aging are also preventing the action of those T cells.
This is why there's a distinct possibility that a future COVD-19 vaccine, particularly one utilizing the traditional attenuated virus approach, could be less effective in older people than in younger ones.
Given the extreme urgency of developing vaccines that work well for everyone, we need to make sure that researchers are exploring all of the ways our elders can be best protected. While generating a vaccine that works equally well for people of all ages would be ideal, we can't count on that.
One way to bridge this gap might be to trick the bodies of older people into behaving as if they are younger just at the moment what a vaccine is delivered by giving them pre-immunization boosters.
Two recent phase 2 studies in older adults have suggested that a new category of drugs called rapalogues can in some cases increase the immunization capacity of older adults. Use of the drug for a short time period before flu shot immunization increased the antibody production for the flu and resulted in a 52 percent decrease in the occurrence of severe diseases needing medical help or hospitalization. This short-term pre-immunization intervention can also decrease the severity of serious respiratory tract infections, the deadliest manifestations of COVID-19, by similar magnitude. These patients also had almost half the incidence of the non-COVID-19 coronaviruses associated with the common cold.
The fact that those people were protected by treatment before hospitalization suggests metformin may have a role in boosting the vaccination of older people.
An inexpensive generic drug called metformin similarly targets the decline in immunity and inflammation (and extends health span and lifespan) in animals and has been used for decades to protect against the flu. A recent paper from a hospital in Wuhan, China showed that mortality of elderly COVID-19 diabetic patients on metformin was 25 percent less than that of patients with diabetes but not on metformin.
Another study from the U.S. showed that COVID-19 patients on metformin had a 20 percent decrease in mortality and lower inflammation. The fact that those people were protected by treatment before hospitalization suggests metformin may have a role in boosting the vaccination of older people.
We don't yet know whether rapalogues or metformin could be used as COVID-19 immunization boosters, not least because we don't have those vaccines. But we can and should make sure that all vaccine trials including older subjects also consider offering a subset of those subjects appropriate doses of rapalogues or metformin to explore whether doing so can boost the efficacy of a given vaccine.
If we weren't in the middle of the worst pandemic in a century, we would have more time to test our vaccines slowly and sequentially. In the context of the current crisis, however, testing whether immunization boosters might increase the efficacy of potential COVID-19 vaccines for older adults is at the very least a hypothesis worth exploring.
How We Can Return to Normal Life in the COVID-19 Era
I was asked recently when life might return to normal. The question is simple but the answer is complex, with many knowns, lots of known unknowns, and some unknown unknowns. But I'll give it my best shot.
To get the fatality rate down to flu-like levels would require that we cut Covid-19 fatalities down by a factor of 5.
Since I'm human (and thus want my life back), I might be biased toward optimism.
Here's one way to think about it: Is there another infection that causes sickness and death at levels that we tolerate? The answer, of course, is 'yes': influenza.
According to the Centers for Disease Control, from 2010 to 2019, an average of 30 million Americans had the flu each year, leading to an annual average of 37,000 deaths. This works out to an infection-fatality rate, or IFR, of 0.12 percent. We've tolerated that level of illness death from influenza for a century.
Before going on, let's get one thing out of the way: Back in March, Covid-19 wasn't, as some maintained, "like the flu," and it still isn't. Since then, the U.S. has had 3.9 million confirmed Covid-19 cases and 140,000 deaths, for an IFR of 3.6 percent. Taking all the cases — including asymptomatic patients and those with minimal symptoms who were never tested for Covid-19 — into account, the real IFR is probably 0.6 percent, or roughly 5 times that of the flu.
Nonetheless, even a partly effective vaccine, combined with moderately effective medications, could bring Covid-19 numbers down to a tolerable, flu-like, threshold. It's a goal that seems within our reach.
Chronic mask-wearing and physical distancing are not my idea of normal, nor, I would venture to guess, would most other Americans consider these desirable states in which to live. We need both now to achieve some semblance of normalcy, but they're decidedly not normal life. My notion of normal: daily life with no or minimal mask wearing, open restaurants and bars, ballparks with fans, and theaters with audiences.
My projection for when we might get there: perhaps a year from now.
To get the fatality rate down to flu-like levels would require that we cut Covid-19 fatalities down by a factor of 5, via some combination of fewer symptomatic cases and a lower chance that a symptomatic patient will go on to die. How might that happen?
First, we have to make some impact on young people – getting them to follow the public health directives at higher rates than they are currently. The main reason we need to push younger people to stay safe is that they can spread Covid-19 to vulnerable people (those who are older, with underlying health problems). But, once the most vulnerable are protected (through the deployment of some combination of effective medications and a vaccine), the fact that some young people aren't acting safely – or maybe won't take a vaccine themselves – wouldn't cause so much concern. The key is whether the people at highest risk for bad outcomes are protected.
Then there's the vaccine. The first principle: We don't need a 100 percent-effective vaccine injected into 320 million deltoid muscles (in the U.S. alone). Thank God, since it's fanciful to believe that we can have a vaccine that's 100 percent effective, universally available by next summer, and that each and every American agrees to be vaccinated.
How are we doing in our vaccine journey? We've been having some banner days lately, with recent optimistic reports from several of the vaccine companies. In one report, the leading candidate vaccine, the one effort being led by Oxford University, led to both antibodies and a cellular immune response, a very helpful belt-and-suspenders approach that increases the probability of long-lasting immunity. This good news comes on the heels of the positive news regarding the American vaccine being made by Moderna earlier in July.
While every article about vaccines sounds the obligatory cautionary notes, to date we've checked every box on the path to a safe and effective vaccine. We might not get there, but most experts are now predicting an FDA-approvable vaccine (more than 50 percent effective with no show-stopping side effects) by early 2021.
It is true that we don't know how long immunity will last, but that can be a problem to solve later. In this area, time is our friend. If we can get to an effective vaccine that lasts for a year or two, over time we should be able to discover strategies (more vaccine boosters, new and better medications) to address the possibility of waning immunity.
All things considered, I'm going to put my nickel down on the following optimistic scenario: we'll have one, and likely several, vaccines that have been proven to be more than 50 percent effective and safe by January, 2021.
If only that were the finish line.
Once we vaccinate a large fraction of high-risk patients, having a moderate number of unvaccinated people running around won't pose as much threat.
The investments in manufacturing and distribution should pay off, but it's still inconceivable that we'll be able to get vaccines to 300 million people in three to six months. For the 2009 Swine Flu, we managed to vaccinate about 1 in 4 Americans over six months.
So we'll need to prioritize. First in line will likely be the 55 million Americans over 65, and the six to eight million patient-facing healthcare workers. (How to sort priorities among people under 65 with "chronic diseases" will be a toughie.) Vaccinating 80-100 million vulnerable people, plus clinicians, might be achievable by mid-21.
If we can protect vulnerable people with an effective vaccine (with the less vulnerable waiting their turn over a subsequent 6-12 month period), that may be enough to do the trick. (Of course, vulnerable people may also be least likely to develop immunity in response to a vaccine. That could be an Achilles' heel – time will tell.)
Why might that be enough? Once we vaccinate a large fraction of high-risk patients, having a moderate number of unvaccinated people running around won't pose as much threat. Since they're at lower risk, they have a lower chance of getting sick and dying than those who received the vaccine first.
We're likely to have better meds by then, too. Since March, we've discovered two moderately effective medications for Covid-19 — remdesivir and dexamethasone. It seems likely that we'll find others by next summer, perhaps even a treatment that prevents patients from getting ill in the first place. There are many such therapies, ranging from zinc to convalescent plasma, currently being studied.
Moreover, we know that hospitals that are not overrun with Covid-19 have lower mortality rates. If we've gotten a fairly effective vaccine into most high-risk people, the hospitals are unlikely to be overwhelmed – another factor that may help lower the mortality rate to flu-like levels.
All of these factors – vaccination of most vulnerable people, one or two additional effective medications, hospitals and ICU's that aren't overwhelmed – could easily combine to bring the toll of Covid-19 down to something that resembles that of the flu. Then, we should be able to return to normal life.
Whatever the reason, if enough people refuse the vaccine, all bets are off.
What do I worry about? There's the growing anti-vaxxer movement, for one. On top of that, it seems that many Americans worry that a vaccine discovered in record speed won't be safe, or that the FDA approval process will have been corrupted by political influences. Whatever the reason, if enough people refuse the vaccine, all bets are off.
Assuming only high-risk people do get vaccinated, there will still be cases of Covid-19, maybe even mini-outbreaks, well into 2021 and likely 2022. Obviously, that's not ideal, and we should hope for a vaccine that results in the complete eradication of Covid-19. But the point is that, even with flu-like levels of illness and death, we should still be able to achieve "normal."
Hope is not a strategy, as the saying goes. But it is hope, which is more than we've had for a while.