Does Coffee Increase Lifespan?

A 2022 observational study publicized by Harvard Health claimed that drinking coffee could significantly lower your risk of dying.

Is that true?

Wasn’t there a study (or ten) in recent memory claiming that coffee would give you cancer?

Well, it turns out observational studies are not very good for studying things like this.

Can updated boosters prevent another Covid-19 surge? Why some experts are skeptical.

Most experts agree that updated bivalent Covid-19 boosters provide additional protection against serious illness and death among vulnerable populations—but evidence suggests that increased booster uptake may not prevent a “wave of Covid” infections this winter, Apoorva Mandavilli writes for the New York Times.

Can bivalent boosters prevent another surge of infections?

While the Biden administration’s plan to prevent another surge of Covid-19 infections relies on increasing Americans’ uptake of the updated booster doses of the PfizerBioNTech and Moderna vaccines, some experts doubt the strategy.

According to John Moore, a virologist at Weill Cornell Medicine, boosters provide additional protection to vulnerable populations—including older adults, immunocompromised individuals, and pregnant people—who should get boosted to prevent severe illness and death.

However, the benefit is not as clear for healthy, younger Americans who “are rarely at risk of severe illness or death from Covid, and at this point most have built immunity through multiple vaccine doses, infections or both,” Mandavilli writes.

“If you’re at medical risk, you should get boosted, or if you’re at psychological risk and worrying yourself to death, go and get boosted,” Moore said. “But don’t believe that will give you some kind of amazing protection against infection, and then go out and party like there’s no tomorrow.”

Separately, Peter Marks, FDA‘s top vaccine regulator, noted the limited data available data for the updated boosters.

“It’s true, we’re not sure how well these vaccines will do yet against preventing symptomatic disease,” he said, especially as the newer variants spread.

However, Marks added, “even modest improvements in vaccine response to the bivalent boosters could have important positive consequences on public health. Given the downside is pretty low here, I think the answer is we really advocate people going out and consider getting that booster.”

How much additional protection do updated shots provide?

While Pfizer-BioNTech and Moderna recently reported that their bivalent boosters produced antibody levels that were four to six times higher than the original vaccine, their results were based on BA.4 and BA.5 antibodies, instead of the more prevalent BQ.1 and BQ.1.1 variants.

According to Mandavilli, “[a] spate of preliminary research suggests that the updated boosters, introduced in September, are only marginally better than the original vaccines at protecting against the newer variants — if at all.”

These small studies have not been reviewed for publication in a journal—but they all came to similar conclusions.

“It’s not likely that any of the vaccines or boosters, no matter how many you get, will provide substantial and sustained protection against acquisition of infection,” said Dan Barouch, head of Beth Israel Deaconess Center for Virology and Vaccine Research, who helped develop Johnson & Johnson‘s vaccine.

Notably, Barouch’s team recently discovered that BQ.1.1 is around seven times more resistant to the body’s immune defenses than BA.5, and 175 times more resistant than the original strain of the coronavirus. “It has the most striking immune escape, and it’s also growing the most rapidly,” he said. BQ.1 will likely follow a similar pattern.

“By now, most Americans have some degree of immunity to the coronavirus, and it does not surprise scientists that the variant that best evades the body’s immune response is likely to outrun its rivals,” Mandavilli writes.

The new vaccine increases antibodies, but the fact it is bivalent may not be significant. In August, a study by Australian immunologists suggested that any kind of booster would offer extra protection. In addition, the study noted that a variant-specific booster would likely not be more effective than the original vaccine.

“The bulk of the benefit is from the provision of a booster dose, irrespective of whether it is a monovalent or bivalent vaccine,” according to the World Health Organization.

Florian Krammer, an immunologist at the Icahn School of Medicine at Mount Sinai, noted that despite recent research, which evaluated immune response soon after vaccination, immune response may improve over time.

“We will see with larger studies and studies at a later time point if there is a good or a significant benefit, but I think it’s certainly not worse,” he added. “I don’t see much risk when you get the vaccine, so you might as well get the benefit.”

“What we need to do right now to get us through the next few months when I think we are in yet another wave of incipient wave of Covid,” Marks added. “And then we need to look forward, and lean into how we’re going to do things differently moving forward.”

Will we see an increase in vaccine uptake?

Currently, FDA allows the booster dose at least two months after a Covid-19 infection or previous does. However, some studies suggest boosting too early could have negative consequences. “Lengthening the interval between boosts to five or six months may be more effective, giving the immune system more time to refine its response,” Mandavilli writes.

Still, “adding yet another shot to the regimen seems unlikely to motivate Americans to opt for the immunization,” no matter the schedule, she adds.

“Each new booster we roll out is going to have a lower and lower uptake, and we’re already pretty close to the floor,” said Gretchen Chapman, an expert in health behavior at Carnegie Mellon University.

Ultimately, “[w]e should not spend a lot of political capital trying to get people to get this bivalent booster, because the benefits are limited,” Chapman added. “It’s more important to get folks who never got the initial vaccine series vaccinated than to get people like me to get their fifth shot.” 

Colonoscopies fail to reduce colon cancer deaths in landmark study

In a randomized controlled trial (RCT) study of 85K Europeans, published this week in the New England Journal of Medicine, colonoscopies were found to reduce incidence of colorectal cancer by only 18 percent—much less than earlier large studies—and have no impact on ten-year colorectal cancer mortality rates. This is the first study to directly compare individuals invited to receive colonoscopies with a control group receiving no cancer screening.

While the study’s findings surprised many researchers, an important caveat to the headline takeaways is that a secondary analysis of study participants who actually completed their colonoscopies found a 50 percent reduction in death, though the decision to accept the invitation likely correlates with other factors that improve mortality outcomes. 

The Gist: We were surprised to learn this was the first RCT to assess the effectiveness of colonoscopies—15M of which are performed in the US each year—and which comprise a $36B market. While the study’s results need careful interpretation, it reminds us that much of established medical consensus has yet to be “proven” by rigorous scientific research. 

While we don’t expect this study’s results to significantly change colonoscopy recommendations, it does place greater emphasis on the question of value generated by widespread preventative screenings. Colonoscopy will almost certainly remain the gold standard for colon cancer screening in the US, but if these results bear out, other less invasive types of screening, like home-based fecal immunochemical testing, could be viewed as equivalent options and receive more traction. 

Longtime HIV patient is effectively cured after stem cell transplant

A 66-year-old man with HIVis in long-term remission after receiving a transplant of blood stem cells containing a rare mutation, raising the prospect that doctors may someday be able to use gene editing to re-create the mutation and cure patients of the virus that causes AIDS, a medical team announced Wednesday.

For now, the crucial virus-defeating mutation is rare, leaving the treatment unavailable to the vast majority of the 38 million patients living with HIV, including over 1.2 million in the United States. Bone marrow transplants also carry significant risk and have been used only on HIV patients who have developed cancer.

The patient, who had lived more than half his life with the virus, is among a handful of people who went into remission after receiving stem cells from a donor with the rare mutation, said doctors from City of Hope, a cancer and research center in Duarte, Calif., who treated him.

“This is one step in the long road to cure,” said William Haseltine, a former Harvard Medical School professor, who founded the university’s cancer and HIV/AIDS research departments. Haseltine, now chairman and president of the nonprofit think tank Access Health International, was not involved in the City of Hope case.

While the announcement at the 24th International AIDS Conference in Montreal does not have immediate implications for most people living with HIV, it continues the long, slow progression of treatment that began with federal approval of the drug AZT in 1987, advanced a decade later with the use of protease inhibitors to reduce the virus in the body, and went further in 2012, with the approval of PrEP, which protects healthy people from becoming infected.

As a result of those developments,an HIV patient diagnosed at around age 20 today can receive antiretroviral therapy and live another 54 years, according to a 2017 study in the journal AIDS.

“When I was diagnosed with HIV in 1988, like many others, I thought it was a death sentence,” said the City of Hope patient, who asked not to be identified, in a statement shared by the hospital. “I never thought I would live to see the day that I no longer have HIV.”

The man received the transplant in early 2019, but continued taking antiretroviral therapy until he had been vaccinated against covid-19. He has been in remission for almost a year and a half.

“He’s doing great,” said Jana T. Dickter, an associate clinical professor in the division of infectious diseases at City of Hope, who presented the data at the conference. “He’s in remission for HIV.”

Dickter said the patient is being treated for painful ulcers in his mouth caused by the donor’s stem cells attacking his tissue.

The patient received the transplant from an unrelated donor in 2019, after being diagnosed with acute myelogenous leukemia. His doctor at City of Hope chose donor stem cells that had a genetic mutation found in about 1 in 100 people of northern European descent.

Those having the mutation, known as CCR5- delta 32, cannot be infected by HIV because it slams shut the doorway used by the virus to enter and attack the immune system. That doorway is the cell receptor CCR5, which the virus uses to enter white blood cells that form an important part of the body’s defense against disease.

The City of Hope patient is among a small, select group of HIV patients to go into remission after receiving such a transplant.

“This is probably the fifth case in which this type of transplant appeared to cure someone. This approach clearly works. It’s curative and we know the mechanism,” said Steven Deeks, a professor of medicine at the University of California at San Francisco, who cared for the first such patient, Timothy Ray Brown. In 2007, Brown was cured by a medical team in Berlin using a transplant from someone who hadthe same mutation.

Following the transplant, Brown no longer had a detectable level of HIV in his blood. He was known as “the Berlin patient” until he released his name in 2010 and moved to San Francisco.

“I will not stop until HIV is cured,” Brown vowed in a 2015 essay in the journal AIDS Research and Human Retroviruses. Brown died in September 2020 of leukemia unrelated to his HIV. He was 54.

Similar successes followed in patients in London, Düsseldorf, Germany and New York.

“It is yet another case that resembles Timothy Brown from years ago,” emailed David D. Ho, one of the world’s leading AIDS researchers and director of the Aaron Diamond AIDS Research Center at Columbia University. “There are several others as well, each using approaches that are not feasible for most infected patients.”

The other patients also received bone marrow transplants, a relatively risky procedure that involves wiping out the patient’s immune system with chemotherapy drugs. Chemotherapy destroys remaining cancer cells, makes room in the marrow for the donor cells and reduces the likelihood that they will come under attack from the immune system. The transplanted blood stem cells are then injected into the bloodstream and make their way to the marrow, where — ideally — they begin producing new, healthy blood cells.

Although the survival rate for bone marrow transplant recipients has risen significantly, 30 percent of the patientsdie within a year of the procedure.

“I think it’s highly feasible to identify appropriate donors — in particular when more people register as bone marrow donors, with more representation of different racial and ethnic backgrounds,” said Eileen Scully, associate professor of medicine at Johns Hopkins University School of Medicine.“That will enable this type of approach to be used for more people.”

But she added that “bone marrow transplantation is a significant medical procedure that carries its own risks.”

Doctors at City of Hope said they prepared the HIV patient for the transplant by giving him a lower-intensity regimen of chemotherapy developed by the cancer center and used with older patients.

HIV patients in wealthy countries like the United States,where antiretrovirals are widely available, live longer, but they also run a higher risk of developing certain cancers such as leukemia. In addition, they have a higher risk of developing heart disease, diabetes and even some brain conditions.

Dickter said that when the City of Hope patient was diagnosed with acute myelogenous leukemia in 2019, his doctors searched for a bone marrow match that contained the HIV-resistant mutation.

The nonprofit National Marrow Donor Program, now routinely screens donors to learn whether they have the CCR5- delta 32 mutation, said Joseph Alvarnas, a City of Hope hematologist-oncologist and a co-author of the abstract.

The possibility of someday being able to effectively cure much large numbers of people by using gene-editing techniques to generate the mutation may be a decade off, Deeks said.

Deeks said he is working with a San Francisco-based company called Excision BioTherapeutics to develop the first-in-human trials that would involve editing the genes of patients with HIV. Studies have shown some success in editing genes inside mice and monkeys infected with HIV.

Deeks said that it is not hardin the lab to use a gene-editing tool to knock out the receptor that allows HIV to invade the immune system. Carrying out that task inside the body of a human patient is where the work gets complex.

“That’s the challenge — to do that effectively and safely,” Deeks said. “And that’s a whole can of worms.”

Haseltine said that researchers must figure out how to reach enough of the right cells inside the body. At the same time, they must ensure the treatment does not cause unwanted effects to other genes.

“The message to people living with HIV is that this is a signal of hope,” said Scully of Johns Hopkins.“It is feasible. It has been replicated again. It’s also a signal that the scientific community is really engaged with trying to solve this puzzle.”

BA.5 spurs new calls to fund next-generation COVID-19 vaccines

The rise of the BA.5 variant is spurring new calls for funding for an Operation Warp Speed 2.0 to accelerate development of next-generation COVID-19 vaccines that can better target new variants. 

The BA.5 subvariant of omicron that now makes up the majority of U.S. COVID-19 cases is sparking concern because it has a greater ability to evade the protection of current vaccines than past strains of the virus did.

Pfizer and Moderna are working on updated vaccines that target BA.5 that could be ready this fall, but experts say that by the time they are ready, a new variant very well could have taken hold.  

As alternatives to vaccine makers chasing each variant, experts point to research on “pan-coronavirus” vaccines that are “variant-proof,” targeting multiple variants, as well as nasal vaccines that could drastically cut down on transmission of the virus.

There is ongoing research on these next-generation vaccines, but unlike in 2020, when the federal government’s Operation Warp Speed helped speed the development of the original vaccine, there is less funding and assistance this time around.  

COVID-19 funding that could help develop and manufacture new vaccines more quickly has been stalled in Congress for months.

“There’s no Operation Warp Speed,” said Eric Topol, professor of molecular medicine at Scripps Research. “So it’s moving very slowly. But at least it’s moving.” 

Leana Wen, a public health professor at George Washington University, wrote in a Washington Post op-ed this week that the U.S. needs “urgent investment” in next-generation vaccines and “we need an ‘Operation Warp Speed Part 2.’” 

Pfizer and Moderna are working on updated vaccines that target BA.5 that could be ready this fall, but experts say that by the time they are ready, a new variant very well could have taken hold.  

As alternatives to vaccine makers chasing each variant, experts point to research on “pan-coronavirus” vaccines that are “variant-proof,” targeting multiple variants, as well as nasal vaccines that could drastically cut down on transmission of the virus.

There is ongoing research on these next-generation vaccines, but unlike in 2020, when the federal government’s Operation Warp Speed helped speed the development of the original vaccine, there is less funding and assistance this time around.  

COVID-19 funding that could help develop and manufacture new vaccines more quickly has been stalled in Congress for months.

“There’s no Operation Warp Speed,” said Eric Topol, professor of molecular medicine at Scripps Research. “So it’s moving very slowly. But at least it’s moving.” 

Leana Wen, a public health professor at George Washington University, wrote in a Washington Post op-ed this week that the U.S. needs “urgent investment” in next-generation vaccines and “we need an ‘Operation Warp Speed Part 2.’” 

Administration health officials pointed to funding when asked about next-generation vaccines at a press briefing on Tuesday.

“We need resources to continue that effort and to accelerate that effort,” said Anthony Fauci, the government’s top infectious disease expert. “So although we’re doing a lot and the field looks promising, in order to continue it, we really do need to have a continual flow of resources to do that.” 

But COVID-19 funding has been stuck in Congress for months. Republicans have long said they do not see any urgency in approving the money. Democrats, while generally calling for the funding, have been caught up in their own internal divisions, like when a group of House Democrats objected to a way to pay for the new funding in March.

“Of course more funding would accelerate some parts of the development,” Karin Bok, acting deputy director of the National Institutes of Health’s (NIH) Vaccine Research Center, said in an interview.  

She also cautioned that development of next-generation vaccines like nasal vaccines would take longer than the original vaccines, because less groundwork has been laid over the preceding years.  

Experts stress that even for BA.5, the current vaccines still provide important protection against severe disease and hospitalization, and are urging people to get their booster shots now. But there is potential for further improvement in the vaccines as well.

Aside from funding, another obstacle is obtaining copies of the existing COVID-19 vaccines for use in research, said Pamela Bjorkman, a California Institute of Technology professor working on a next-generation vaccine. 

“I would say we’ve wasted at least six months,” with various procedural hurdles on that front, she said. “It’s just ridiculous.” 

For example, she said at one point when her team was able to get access to the AstraZeneca COVID-19 vaccine, it then took two or three months to get an import permit to send it from the United Kingdom.

“This is a hot topic,” Bok, of the NIH, said of access to existing vaccine doses for researchers. “The government is working very hard on an agreement with the companies to provide it to us and to all the investigators…that are funded by NIH.” 

Asked about providing vaccine doses for researchers and any talks with the administration on that front, a Moderna spokesperson said: “We do provide vaccine in certain investigator-initiated studies where physicians and scientists propose research they have designed and want to conduct with our support,” pointing to a South African study as an example.  

More broadly, the White House says it is working on accelerating next-generation vaccine research and will have more announcements soon.  

“Let me be very clear: We clearly need a true next-generation vaccine,” White House COVID-19 response coordinator Ashish Jha told reporters on Tuesday. 

“You’ll hear more from us in the days and weeks ahead,” he added. “This is something that we have been working quite assiduously on.” 

COVID vaccine strategy still murky after FDA experts meet

The COVID-19 vaccine strategy for the fall remains beset with unanswered questions after an FDA expert panel on Tuesday spent hours debating how and whether to update the shots.

Why it matters: Time is running short to develop a game plan with existing vaccines losing effectiveness against new variants and more than half of Americans still without a booster dose.

Driving the news: The Vaccines and Related Biological Products Advisory Committee voted 19-2 to recommend an Omicron-specific update to COVID-19 booster vaccines expected to be rolled out within the next few months.

But key questions were left unanswered:

  • The panel didn’t formally decide whether to update shots with the prevalent Omicron strain in circulation, currently the fast-spreading BA.4 and BA.5 subvariants, or the BA.1 lineage that emerged late last year, as the World Health Organization recommended.
  • The consensus appeared to be for a bivalent, or combination, booster combining the original COVID-19 strain that emerged in late 2019 with BA.4 and BA.5.
  • The FDA will continue to evaluate what to do about the primary series of vaccines for the fall.
  • Experts were split on whether there was enough data to recommend the updated shots for kids, or whether more studies are needed on dosage and possible side effects.
  • There also were concerns about what effect an updated vaccine would have on developing nations’ willingness to use older COVID shots to inoculate their populations.
  • And above all, it’s unclear whether all the questions about who gets which shot when will add to public confusion and apathy that’s dogged the vaccination effort in recent months.

What they’re saying: “None of us has a crystal ball and we’re trying to use every last ounce of what we can from predictive modeling and data that’s emerging to try to get ahead of a virus that’s very crafty,” said top FDA vaccine regulator Peter Marks.

  • “Unfortunately, looking in the past doesn’t help us a great deal to look in the future for [a] virus that has baffled a lot of us and made predictions almost irrelevant,” said acting panel chairman Arnold Monto, a University of Michigan epidemiologist.

The timetable: Pfizer-BioNTech said an updated mRNA vaccine could be ready in October if regulatory uncertainties are ironed out. Moderna said it could have large amounts ready in late October or early November. Novavax is still awaiting emergency use authorization for its protein-based shot, but said it could have an updated vaccine by the fourth quarter.

‘The first time this has happened in the history of cancer’

In a “small but compelling” study published Sunday in the New England Journal of Medicine, 18 patients with rectal cancer achieved complete remission, marking “the first time this has happened in the history of cancer,” Gina Kolata reports for the New York Times.

Key takeaways: Defining and assessing value for next-generation therapies

Study details and key findings

For the trial, which was sponsored by GlaxoSmithKline, 18 patients with rectal cancer took a checkpoint inhibitor called dostarlimab. During the six-month study period, the medication was administered every three weeks. Dostarlimab works by exposing cancer cells, allowing the immune system to detect and destroy them.

Before the trial, “[t]hese rectal cancer patients had faced grueling treatments — chemotherapy, radiation and, most likely, life-altering surgery that could result in bowel, urinary and sexual dysfunction,” Kolata writes. “Some would need colostomy bags.”

When the trial began, many of the patients still believed they would have to undergo these procedures when it was over. Ultimately, no one really believed their tumors would disappear.

However, they were met with “astonishing” results, Kolata writes. “The cancer vanished in every single patient, undetectable by physical exam, endoscopy, PET scans or M.R.I. scans.”

“There were a lot of happy tears,” said Andrea Cercek, an oncologist at Memorial Sloan Kettering Cancer Center (MSKCC) and a co-author of the paper, which was presented Sunday at the annual meeting of the American Society of Clinical Oncology.

On average, one in five patients have some type of adverse reaction to checkpoint inhibitors like dostarlimab. But, notably, none of the patients in the trial experienced clinically significant complications.


According to Alan Venook, a colorectal cancer specialist at the University of California, San Francisco, who was not involved with the study, the absence of significant side effects means “either they did not treat enough patients or, somehow, these cancers are just plain different.”

In an editorial accompanying the paper, Hanna Sanoff of the University of North Carolina‘s Lineberger Comprehensive Cancer Center, who was not involved in the study, said the study was “small but compelling.” However, she noted that it is still unclear whether the patients are cured.

“Very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” Sanoff said.

And while the results were “remarkable” and “unprecedented,” Kimmie Ng, a colorectal cancer expert at Harvard Medical School, said they would need to be replicated.

Still, Luis Diaz Jr., an author of the paper from MSKCC, said he did not know of any other study in which a treatment completely eradicated a cancer in every patient.

“I believe this is the first time this has happened in the history of cancer,” Diaz said.

Separately, Venook agreed, noting that a complete remission in every single patient in a trial is “unheard-of.” (Kolata, New York Times, 6/5)

Biden’s $5.8 trillion budget: 9 healthcare takeaways

President Joe Biden proposed a $5.8 trillion budget March 28 for fiscal year 2023, which includes funding for healthcare. 

Nine healthcare takeaways:

1. Pandemic preparedness. The budget calls for a five-year investment of $81.7 billion to plan ahead for future pandemics. The funding would help support research and development of vaccines, improve clinical trial infrastructure and expand domestic manufacturing. 

2. Mental health parity. Under the proposed budget, federal regulators would get the power to levy fines against health plans that violate mental health parity rules. The budget calls for $275 million over 10 years to increase the Labor Department’s capacity to ensure health plans are complying with the requirements and take action against those plans that do not. The budget also proposes funding to bolster the mental healthcare workforce and boost funding for suicide prevention programs. 

3. Vaccines for uninsured adults. The proposed budget calls for establishing a new Vaccines for Adults program that would provide uninsured adults access to recommended vaccines at no cost.

4. Title X funding. The budget proposes providing $400 million in funding for the Title X Family Planning Program, which provides family planning and other healthcare services to low-income individuals.

5. Cancer Moonshot initiative. The budget proposes several investments across the FDA, CDC, National Cancer Institute and Advanced Research Projects Agency for Health to advance President Biden’s Cancer Moonshot initiative. The initiative aims to reduce the cancer death rate by 50 percent over the next 25 years. 

6. Spending to reduce HIV. The proposed budget includes $850 million to reduce new HIV cases by increasing access to HIV prevention services and support services.

7. Veterans Affairs medical care. President Biden’s proposed budget allocates $119 billion, or a 32 percent increase, to medical care for veterans. The money will fully fund inpatient, outpatient, mental health and long-term care services, while also investing in training programs for clinicians to work in the VA.

8. Discretionary funding for HHS. President Biden is asking Congress to approve $127.3 billion in discretionary funding for HHS in fiscal 2023, representing a $26.9 billion increase from the department’s allotment for fiscal 2021.

9. Mandatory spending for the Indian Health Service. The budget request for the Indian Health Service calls for shifting the healthcare agency from discretionary to mandatory funding. The budget calls for $9.1 billion in funding, a 20 percent increase from the amount allocated in fiscal 2021.

COVID-19 May Be Linked to Spontaneous Psychosis. Researchers Are Trying to Figure Out Why

In May 2020, a 33-year-old mother of three in North Carolina started experiencing symptoms of COVID-19. Four days later, a different set of symptoms set in. She stopped sleeping well and started having paranoid delusions that people were tracking her through her cell phone—culminating in a frantic scene at a fast-food restaurant, in which she tried to pass her children through the drive-through window, where they’d be safe from the phones and other dangers.

A restaurant employee called 911, and emergency medical services workers arrived, gathered up the family, and hurried to the nearby emergency department of the Duke University Medical Center in Durham, where the mother was quickly attended to by physicians. “She was physically in the room, but she wasn’t making consistent eye contact,” says Dr. Colin Smith, who is now chief resident of the hospital’s internal medicine psychiatry program but was a second-year resident when he took care of the patient. “She was not really engaging all that much. Her thought processes were disorganized.”

Despite that, the patient acknowledged two things to Smith and the other doctors: She knew her behavior was out of character, and the changes all happened quickly after she was diagnosed with COVID-19.

There’s growing evidence that COVID-19 and new psychotic episodes are connected. The North Carolina case, reported in the British Medical Journal in August 2020, joins a slew of case reports published in medical journals during the pandemic that detail psychotic episodes following a COVID-19 diagnosis. In the July 2020 issue of BJPsyh Open, researchers reported that a 55-year old woman in the U.K., with no history of mental illness, arrived at a hospital days after recovering from a severe case of COVID-19 with delusions and hallucinations, convinced that the nurses were devils in disguise and that monkeys were jumping out of the doctors’ medical bags. In April 2021, other researchers wrote in BMJ Case Reports of a middle-aged British man, also with no prior mental health disorders, who had appeared at a London hospital experiencing auditory and visual hallucinations and banging his head against walls until he bruised his skin. (Weeks before, he had recovered from a bout with COVID-19 that had landed him in the intensive care unit.) In yet another case, published in the Journal of Psychiatric Practice in March 2021, a 57-year-old-man turned up at Columbia University’s New York Presbyterian Hospital insisting that his wife was poisoning him, that cameras had been planted throughout his apartment, and that the patients in the hospital’s emergency department were being secretly murdered.

“The situation was strikingly similar to one we’d expect from someone who had a schizophrenia spectrum illness,” says Dr. Aaron Slan, now a fourth-year psychiatry resident at Columbia University, who cared for the patient and co-authored the report. But this patient too had no history of mental health disorders and was too old for a first-onset case of schizophrenia, which typically occurs between ages 20 and 30 for men, Slan notes. What the patient did have, as a test in the hospital revealed, was COVID-19.

COVID-19-related psychotic breaks are rare—though researchers say that it’s too early to say exactly how rare—and plenty of experts believe that the connection between the two conditions, if any, is not causal. In a review published in 2021 in Neurological Letters, a group of researchers in the U.K. casts doubt on the emerging body of work on the COVID-19-psychosis link as “beset by both small sample size, and inadequate attention to potential confounding factors,” such as heightened stress, substance abuse, and socioeconomic hardship.

Still, researchers are investigating the link. One U.K. study published in the Lancet in October 2020 found that of 153 people who were diagnosed with COVID-19 early in the pandemic, 10 suffered new-onset psychotic episodes following their COVID-19 diagnosis, and seven exhibited the onset of psychiatric disorders, including catatonia and mania.

A study published last August in General Hospital Psychiatry took a broad view of the phenomenon, analyzing 40 scientific articles, which included 48 adults from 17 different countries who suffered psychotic episodes associated with COVID-19 infection, and tried to find commonalities among them. As with the Neurological Letters paper, the authors of this study found plenty of other variables that might muddy the link between COVID-19 and psychosis—like stress, substance use, and medications—but the relationship still held.

We see post-infectious neuroinflammatory disorders associated with a variety of different viral illnesses,” says Dr. Samuel Pleasure, a neurology professor at the University of California, San Francisco (UCSF). “Normally we see it in very small numbers, but here we have [COVID-19] infecting tens of millions of people at the same time.” Even rare cases of psychiatric conditions will start to show themselves when the sample group of infected people is so large.

There are more questions than answers at this point. It’s still unclear whether the severity of COVID-19 symptoms plays any role in the likelihood of a psychotic break. “There seem to be clearly cases of neuropsychiatric consequences of COVID that are linked to cases that are not severe,” Pleasure says. “I believe that the quality of the studies at this point are so preliminary, and the ability to really capture these patients to study is really at early stages, so it’s hard to be definitive.” Similarly, Pleasure says, it’s impossible to say whether people suffering from Long COVID—symptoms that last for months after the infection is over—are more susceptible to psychotic symptoms.

There are multiple possible mechanisms at work, any one of which—or a combination—could be contributing to the neuropsychiatric symptoms associated with COVID-19. The most straightforward would be direct infection of brain tissue itself, according to Pleasure. If that’s so, the number of COVID-19 patients who suffer loss of the sense of taste and smell would suggest that the brain’s olfactory bulb may be struck by the virus first.

“There are documented cases where people have done MRIs early in the [COVID-19 disease] process and have seen some local inflammation in the olfactory bulb,” Pleasure says. “That has contributed further to the idea that maybe that’s the portal of entry.” Once that portal has been breached, the brain at large could be exposed.

Just how the COVID-19 infection reaches the brain is unclear, but Pleasure and his colleague Dr. Michael Wilson, associate professor of neurology at UCSF, conducted lumbar punctures of three teens with COVID-19 who had developed neuropsychiatric symptoms to examine their cerebrospinal fluid. In two cases, they found antibodies in the fluid that target neural antigens. That presented an apparent puzzle: the patients had SARS-CoV-2; if anything, they should be exhibiting antibodies to the virus, not to their own neural tissue. But Pleasure cites one study he conducted with a group from Yale University showing that antibodies specific to the coronavirus spike protein could also cross-react with nerve cells, attacking them as well.

“There was molecular mimicry between the spike protein and a neural antigen,” he says. “One of the main hypotheses is that if there’s an antibody that targets the virus, then, out of bad luck, you also see damage to the host.” In other words, he says, you start with an immune response adaptive to fighting the virus, and that turns into an autoimmune response.

That’s just one theory. There are still other routes by which COVID-19 can affect the brain. Upper respiratory infections can, on occasion, cause the immune system to go awry and develop antibodies against parts of the brain known as NMDA (N-methyl-D-aspartate) receptors, which are the main excitatory receptors that react to neurotransmitters. A broad attack on receptors spread throughout the brain can lead to quick and severe symptoms, says Dr. Mudasir Firdosi, a Consultant Psychiatrist at the Kent and Medway NHS and Social Care Partnership Trust and a co-author of the 2021 BMJ paper.

“[NMDA involvement] presents a very, very florid way to be psychotic,” Firdosi says. Slan agrees: “When someone has an abrupt onset of psychosis following a viral illness, NMDA antibodies are frequently invoked,” he says.

Yet another suspect in the development of neuropsychiatric symptoms is the so-called cytokine storm that often follows infection with SARS-CoV-2. Cytokines are proteins critical for cell signaling that are produced by the immune system and give rise to inflammation that in turn can fight infection. But if cytokine production spins out of control, extreme body-wide inflammation can follow, and brain tissue would not be spared the impact.

“The neurons themselves are not being invaded,” says Slan, “but what happens is that the systemic inflammatory response causes both stress and changes in signaling throughout the body. That includes the brain, and can precipitate these types of [psychotic] symptoms.”

One other bit of evidence that COVID-19 is linked to psychotic breaks comes not from the current scientific literature, but from history. Following the influenza pandemic of 1918 and 1919, there was a spike in what was called encephalitis lethargica, which was essentially a form of early-onset Parkinson’s disease that often didn’t appear for a number of years after the infection—but left patients in what was effectively a state of catatonia.

“That flu virus caused a post-infection inflammation that killed brain cells that in turn led to the Parkinson’s,” says Pleasure. The book and movie Awakenings, about patients who temporarily recovered consciousness and lucidity after treatment with l-dopa—a precursor of the neurotransmitter dopamine—was based on cases of people suffering from that form of Parkinson’s.

The good news is that unlike more chronic forms of psychosis, most cases seemingly related to COVID-19 do not appear to last. The symptoms can respond to antipsychotic medications like Risperdal (risperidone) and Zyprexa (olanzapine), say Smith and Slan. Intravenous immunoglobulin infusions—which reduce the overall load of abnormal cells and inflammatory agents—and steroids, which also reduce inflammation, can be effective as well.

By no means is the case for virus-triggered psychosis closed. Even Slan, who has first-hand experience treating a patient suffering from a seemingly virus-linked psychotic break believes that there is more work to be done—and acknowledges the doubts of the researchers who believe other psychological factors might be at play.

“Given the stress of COVID,” he says, “given the concerns about mortality, seclusion, all of these things represent huge psychosocial stressors, and they have the potential to precipitate oftentimes short-lived psychotic symptoms.”

Of course, even a transitory psychosis is still a psychosis—something no one wants to experience even fleetingly. That puts a premium on avoiding infection in the first place. “The best way to treat COVID-19 and the risk of psychosis is to prevent it,” says Smith. “Even if neurological complications are rare, getting vaccinated remains the smartest choice.”