There was a time , nobody knew much about inflammatory bowel disease. That’s changing fast. New knowledge is bringing new treatments.
Many of these new approaches have already reached human tests, according to an article in The New England Journal of Medicine.
Some million Americans suffer from Crohn’s disease or ulcerative colitis. These two diseases are known as inflammatory bowel disease. Both are complex illnesses. There’s not just a simple germ involved. The root cause is the interplay between the environment, a person’s genetic makeup, and a person’s immune system.
A major clue to what’s going on came with the 1996 discovery of a gene that makes some people highly vulnerable to Crohn’s disease. The gene has a name — NOD2 — but even now, nobody’s entirely sure what it does to make people sick.
Some say it plays a role in controlling the life cycle of body cells. Others say that NOD2 genes are part of the immune system’s built-in seek-and-destroy germ-killing machinery. Whichever theory is correct, both offer the same kind of clue: both point to the body’s relationship with intestinal flora. Intestinal flora is the bacteria that live in everybody’s gut. We’ve evolved along with them so that we give them a place to grow and they help us survive. All of this is part of a delicate balance. The flora talks to the cells lining the gut, which in turn talks to the cells of the immune system. When this circuit gets broken, it upsets the balance of nature. Inflammatory bowel disease is the result. New treatments would fix this broken circuit. All have worked in animal studies; some are now in human tests. Here are some of the new approaches:
- Drugs that target immune cells in the mucous lining of the intestine. These are a kind of T cell that isn’t getting the right message and is attacking normal cells. Slowing these guys down stops Crohn’s disease in animal studies.
- Fight T cells with T cells. This approach would teach the T cells that regulate the immune response to give the right instructions to the misguided T cells that carry out the attack orders.
- Learn the chemical language of the gut. The right chemical signals would restore order to the inflamed bowel.
- Drugs that would kill off the wrong kinds of bugs living in the gut without harming the good bugs.
- Fight germs with germs. This approach would use genetically engineered “good” bacteria that would turn off harmful immune responses.
Can vitamin D really prevent Covid-19? Here’s what the evidence says.
Vitamin D supplement sales have soared amid the pandemic as people try to curb their risk of contracting the novel coronavirus—but some experts are urging caution, noting that not enough research has been done to establish a definitive relationship between taking the supplement and fending off Covid-19.
What the research says about vitamin D and Covid-19
According to Sabyasachi Sen, a professor of endocrinology and medicine at George Washington University (GW), deficiencies of vitamin D are “not rare” and are especially common in older adults, obese people, and people with darker skin—some of the same populations most affected by Covid-19.
While vitamin D is known for protecting bone health, it also helps with the immune system, Sen said. It’s believed that vitamin D improves the function of certain cells, including T cells, which fight off pathogens and can assist in modulating inflammatory responses.
In addition, Sen continued, research has found vitamin D deficiencies have been associated with an increased risk of infection. “Now, what is unknown is whether it’s a cause and effect rather than an association,” he said.
According to the Washington Post, researchers studying the relationship between vitamin D and Covid-19 outcomes are interested in precisely that question: whether there’s a cause and effect relationship, or merely an association.
For example, one study, published in JAMA Network Open, looked at the health records of 489 people in Chicago and found patients with a vitamin D deficiency in the year prior to testing for Covid-19 were 77% more likely to test positive for the disease than those with normal vitamin D levels. Taking a converse approach, another study looked at a small group of Covid-19 patients in Italy who had been hospitalized with acute respiratory failure and found that 81% of them had a vitamin D deficiency.
Meanwhile, an experimental study in France at a nursing home with 66 people found that taking vitamin D supplements was “associated with less severe Covid-19 and a better survival rate.” Similarly, a study in South Korea of 200 people found that a deficiency of vitamin D could “decrease the immune defenses against Covid-19 and cause progression to severe disease.” And a small study in Spain involving 76 hospitalized Covid-19 patients found that those treated with calcifediol—an activated version of vitamin D, distinct from the over-the-counter supplement—seemed to curb the severity of the disease.
On the flipside, however, a recent paper considered by the National Institute for Health and Care Excellence in the United Kingdom looked at vitamin D levels from up to 14 years ago and didn’t find any correlation between vitamin D levels and Covid-19 mortality. And while the lead author of that study has in other papers called for further research on the link between vitamin D and Covid-19 outcomes, the researchers concluded, “For now, recommendations for vitamin D supplementation to lessen Covid-19 risks appear premature and, although they may cause little harm, they could provide false reassurance leading to changes in behaviour that increase risk of infections.”
Similarly, a double-blind randomized controlled trial of 240 patients in Brazil, which has yet to be peer-reviewed, found that one large dose of vitamin D didn’t reduce hospital stay length or mortality rates among patients with a severe case of Covid-19 compared with those in a placebo group.
Correlation—not necessarily causation
“We do know that people who have lower blood levels of vitamin D tend to have a higher risk of being infected with Covid-19 and having severe Covid-19 illness,” JoAnn Manson, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, said. “But as we say in epidemiology, ‘Correlation doesn’t prove causation.’ We don’t know for sure that the low vitamin D level is causing an increased risk of Covid-19.”
According to Natasha Chida, an infectious disease expert and assistant professor of medicine at Johns Hopkins University, people who have a vitamin D deficiency typically have other health factors that could affect how likely they are to develop a severe case of Covid-19—and people who do develop diseases such as Covid-19 often experience a drop in vitamin D levels.
“Unless you take into account all those factors and separate all those out and look at just vitamin D … it’s really hard to make any inferences about what vitamin D is doing here,” she said.
Chida added that there’s “some biologic plausibility” that vitamin D could help Covid-19 patients. “It’s just that despite years of research into the use of vitamin D in respiratory tract infections, there still hasn’t really been a clear, slam-dunk answer that there’s a benefit.”
Research into the relationship is ongoing, however. According to the Washington Times, about 70 clinical trials assessing vitamin D and Covid-19 have been filed in the U.S. National Library of Medicine database.
Should you take vitamin D supplements?
As of now, experts say people who know they have vitamin D deficiencies should continue their treatment, and those thinking about taking supplements should talk to their health care provider first, given there’s no firm evidence that vitamin D supplements curb people’s risk of infection or serious Covid-19 illness.
“People should be wary of taking mega doses of vitamins or unproven interventions specifically for Covid-19, because we don’t have good quality data yet to suggest that this is of any help,” Hana Akselrod, an infectious disease specialist at GW, said.
Instead of supplements, people can add more vitamin D to their lives by being outdoors for 15 or 20 minutes a day, Akselrod added. And some foods, such fatty fish or fortified dairy products, could also improve vitamin D levels, Manson said.
“There are all of the positive confluences around nutrition and outdoor exercise that aren’t just limited to the number of how many units of vitamin D you get every day,” Akselrod said. “And on top of that, people absolutely need to continue all the other safety precautions, like masking and safe distancing and avoiding gatherings, because we’re in the most dangerous phase of the pandemic yet”.
COVID-19 will likely be with us forever. Here’s how we’ll live with it.
As COVID-19 continues to run its course, the likeliest long-term outcome is that the virus SARS-CoV-2 becomes endemic in large swaths of the world, constantly circulating among the human population but causing fewer cases of severe disease. Eventually—years or even decades in the future—COVID-19 could transition into a mild childhood illness, like the four endemic human coronaviruses that contribute to the common cold.
“My guess is, enough people will get it and enough people will get the vaccine to reduce person-to-person transmission,” says Paul Duplex, director of the University of Pittsburgh’s Center for Vaccine Research. “There will be pockets of people who won’t take [the vaccines], there will be localized outbreaks, but it will become one of the ‘regular’ coronaviruses.”
But this transition won’t happen overnight. Experts say that SARS-CoV-2’s exact post-pandemic trajectory will depend on three major factors: how long humans retain immunity to the virus, how quickly the virus evolves, and how widely older populations become immune during the pandemic itself.
Depending on how these three factors shake out, the world could be facing several years of a halting post-pandemic transition—one marked by continued viral evolution, localized outbreaks, and possibly multiple rounds of updated vaccinations.
“People have got to realize, this is not going to go away,” says Roy Anderson, an infectious disease epidemiologist at Imperial College London. “We’re going to be able to manage it because of modern medicine and vaccines, but it’s not something that will just vanish out of the window.”
The long road to another common cold
One of the essential factors governing the future of COVID-19 is our immunity to the illness. Immunity to any pathogen, including SARS-CoV-2, isn’t binary like a light switch. Instead, it’s more like a dimmer switch: The human immune system can confer varying degrees of partial protection from a pathogen, which can stave off severe illness without necessarily preventing infection or transmission.
In general, the partial protection effect is one of the reasons why the four known endemic human coronaviruses—the ones that cause a common cold—have such mild symptoms. A 2013 study in BMC Infectious Diseases shows that on average, humans are first exposed to all four of these coronaviruses between the ages of three and five-part of the first wave of infections that young children experience.
These initial infections lay the foundation for the body’s future immune response. As new variants of the endemic coronaviruses naturally evolve, the immune system has a head start in fighting them off—not enough to eradicate the virus instantly, but enough to ensure that symptoms don’t progress much beyond the sniffles.
“The virus is also its own enemy. Every time it infects you, it tops up your immunity,” says Marc Veldhoen, an immunologist at the Portugal’s University of Lisbon.
Past studies make clear that partial immunity can keep people from getting seriously ill, even as coronaviruses successfully enter their systems. Long-term, the same is likely to be true for the new coronavirus. Emory University postdoctoral fellow Jennie Lavine modeled SARS-CoV-2’s post-pandemic trajectory based on the 2013 study’s data, and her results—published in Science on January 12—suggest that if SARS-CoV-2 behaves like other coronaviruses, it will likely morph into mild nuisance years to decades from now.
This transition from pandemic to minor ailment, however, depends on how the immune response to SARS-CoV-2 holds up over time. Researchers are actively examining the body’s “immunological memory” of the virus. A study published in Science on January 6 tracked the immune response of 188 COVID-19 patients for five to eight months post-infection, and while individuals are varied, about 95 percent of patients had measurable levels of immunity.
“Immunity is waning, but certainly not gone, and I think this is key,” says Lavine, who wasn’t involved with the study.
In fact, it’s even possible that one of the cold-causing coronaviruses sparked a serious outbreak in the 1800s before fading into the litany of mild, commonplace human pathogens. Based on the spread of its family tree, researchers estimated in 2005 that the endemic coronavirus OC43 entered humans sometime in the late 19th century, likely the early 1890s. The timing has led some researchers to speculate that the original version of OC43 may have caused the “Russian flu” pandemic of 1890, which was noted for its unusually high rate of neurological symptoms—a noted effect of COVID-19.
“There’s no hard proof, but there are a lot of indications that this wasn’t an influenza pandemic but a corona-pandemic,” Veldhoen says.
The crucible of evolution
Though the carnage of past coronaviruses has faded over time, the road to a relatively painless coexistence between humans and SARS-CoV-2 will likely be bumpy. In the medium-term future, the impact of the virus will depend largely on its evolution.
SARS-CoV-2 is spreading uncontrollably around the world, and with every new replication, there’s a chance for mutations that could help the virus more effectively infect human hosts.
The human immune system, while protecting many of us from a serious illness, is also acting as an evolutionary crucible, putting pressure on the virus that selects for mutations that make it bind more effectively to human cells. The coming months and years will reveal how well our immune systems can keep up with these changes.
New SARS-CoV-2 variants also make widespread vaccination and other transmission-blocking measures, such as face masks and distancing, more crucial than ever. The less the virus spreads, the fewer opportunities it has to evolve.
We’re going to be able to manage it because of modern medicine and vaccines, but it’s not something that will just vanish out of the window.
ROY ANDERSONIMPERIAL COLLEGE LONDON
Current vaccines should still work well enough against emerging variants, such as the B.1.1.7 lineage first found in the United Kingdom, to prevent many cases of serious illness. Vaccines and natural infections create diverse swarms of antibodies that glom onto many different parts of SARS-CoV-2’s spike protein, which means that a single mutation can’t make the virus invisible to the human immune system.
Mutations may produce future variants of SARS-CoV-2 that partially resist current vaccines, however. In a preprint posted on November 19 and updated on January 19, Duplex and his colleagues show that mutations that delete parts of the SARS-CoV-2 genome’s spike protein region prevent certain human antibodies from binding.
“What I’ve learned from our own work is how deviously beautiful evolution is,” Duplex says.
Other labs have found that mutations in 501Y.V2, the variant first found in South Africa, are especially effective at helping the virus elude antibodies. Out of 44 recovered COVID-19 patients in South Africa, blood extracts from 21 of the patients didn’t effectively neutralize the 501Y.V2 variant, according to another preprint published on January 19. Those 21 people had mild to moderate cases of COVID-19, however, so their antibody levels were lower, to begin with, perhaps explaining why their blood did not neutralize the 501Y.V2 variant.
So far, currently authorized vaccines—which spur the production of high levels of antibodies—seem to be effective against the most concerning variants. In a third preprint published on January 19, researchers showed that antibodies from 20 people who had received the Pfizer-BioNTech or Moderna vaccines didn’t bind quite as well to viruses with the new mutations as they did to earlier variants—but they still bound, suggesting the vaccines will still protect against severe illness.
The new variants bring other threats as well. Some, such as B.1.1.7, appear to be more transmissible than earlier forms of SARS-CoV-2, and if left to spread uncontrollably, these variants could make many more people severely ill, which risks overwhelming healthcare systems around the world and even higher death tolls. Veldhoen adds that new variants also may pose a greater risk of reinfection to recovered COVID-19 patients.
Researchers are closely monitoring the new variants. If vaccines need to be updated in the future, Anderson says that it could be done quickly—in roughly six weeks for currently authorized mRNA vaccines, such as those made by Pfizer-BioNTech and Moderna. That timetable, though, doesn’t account for the regulatory approvals that updated vaccines would need to go through.
Anderson adds that depending on how the evolution of the virus progresses, lineages of SARS-CoV-2 may arise that are distinct enough that vaccines will need to be tailored to specific regions akin to vaccines for pneumococcus. To successfully guard against SARS-CoV-2 going forward, we will need a global monitoring network similar to the worldwide reference laboratories used to collect, sequence, and study variants of influenza.
“We’re going to have to live with it, we’re going to have to have constant vaccination, and we’re constantly going to have to have a very sophisticated molecular surveillance program to keep track of how the virus is evolving,” Anderson says.
The promise and challenge of widespread vaccination
Experts agree that transitioning beyond a pandemic depends on the prevalence of immunity, especially among older and more vulnerable populations. Younger people, especially children, will build up immunity to SARS-CoV-2 over a lifetime of exposure to the virus. Today’s adults have had no such luxury, leaving their immune systems naive and exposed.
The exact threshold for achieving population-wide immunity that slows down the virus’s spread will depend on how contagious future variants become. But so far, research of early variants of SARS-CoV-2 suggests at least 60 to 70 percent of the human population will need to become immune to end the pandemic phase.
This immunity can be achieved in one of two ways: large-scale vaccination, or recovery from natural infections. But achieving widespread immunity through uncontrolled spread comes at a terrible cost: hundreds of thousands more deaths and hospitalizations around the world. “If we don’t want to push forward vaccines and champion vaccines, we have to decide collectively how many old people we want to die—and I don’t want to be the one making that decision,” Duplex says.
Jeffrey Shaman, an infectious diseases expert at Columbia University, points out that the global push for vaccines also exposes existing inequities in global health. In a widely shared map from December, The Economist Intelligence Unit estimated that rich countries such as the U.S. will have widely accessible vaccines by early 2022, which may not happen for poorer countries in Africa and Asia until as late as 2023.
Efforts to vaccinate the developing world hinge, in part, on vaccines that can be stored with standard refrigeration, such as the vaccines under development by Oxford/AstraZeneca and Johnson & Johnson. (See the latest on COVID-19 vaccine development around the world.)
As of the week of January 18, according to a World Health Organization estimate, some 40 million COVID-19 vaccine doses have been administered around the world, mostly in high-income countries. In Africa, only two countries, Seychelles and Guinea, have started providing vaccines. And in Guinea, a low-income country, only 25 people have received doses.
Patients with IBD should receive COVID-19 vaccine, despite concerns
“For patients with IBD we would advocate, based on [International Organization for the Study of Inflammatory Bowel Disease (IOIBD)], that patients get vaccinated, acknowledging that there is a lack of data specifically in IBD patients,” Ryan C. Ungaro, MD, MS, gastroenterologist with Mount Sinai Hospital’s Feinstein IBD Center, told Healio Gastroenterology. “But we think the benefits outweigh the risks and based on prior experience with vaccinations in IBD patients.”
CDC and IOIBD recommend patients with IBD should receive the COVID-19 vaccine.
According to Ungaro, the CDC recommended immunocompromised patients should get the COVID-19 vaccine. Patients should be counseled that it is not yet known whether the safety and effectiveness of the vaccine in immunocompromised patients are the same compared with the general population.
“The major concern would be certain medications could lead to decreased response to the vaccine,” he said. “That is something that is going to need to be studied but right now the expert consensus is that IBD patients should get vaccinated against COVID-19.”
According to IOIBD recommendations, patients with IBD should receive the COVID-19 vaccine as soon as possible. Messenger RNA vaccines, replication vector vaccines, inactivated vaccines, and recombinant vaccines are safe to be administered in IBD patients, Ungaro said.
Additionally, the IOIBD said vaccines should not be deferred if an IBD patient is receiving immune-modifying therapies.
According to Ungaro, patients with IBD who take corticosteroids and get the vaccine should receive counseling that there may be a decreased systemic response. He said this needs to be studied further.
“Prospective studies are being planned to look at the real-world effectiveness and side effects of the COVID-19 vaccine in IBD patients,” Ungaro said. “This would require cohorts that are vaccinated and followed. Some studies are ongoing for that both in the United States and internationally. [Surveillance Epidemiology of Coronavirus Under Research Exclusion-IBD (SECURE-IBD)] is going to help support some of these efforts as well.”
Ungaro and his team at Mount Sinai in collaboration with the University of North Carolina developed the SECURE-IBD registry early in 2020 to monitor and report outcomes of COVID-19 in patients with IBD.
He said, “Physicians can encourage IBD patients to enroll in the Crohn’s and Colitis Foundation’s IBD Partners, they will be one of the sources for the prospective COVID-19 vaccine studies.”
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