Immunology

A mix of microbes may help explain why some people develop dry eye disease, new research showed.

This finding suggests that bacteria may cause dry eye and could someday point to new treatments for the condition and related disorders, which affect an estimated 27 million Americans, according to researchers.

Current treatments aim to preserve and enhance tears and tear production to ease the grittiness and itchiness that accompany dry eye disease. 

To examine the role of the ocular microbiome in dry eye disease, scientists in Texas analyzed swab samples from 30 men and women, nine of whom had dry eye.

They found Streptococcus and Pedobacter species were the most common bacteria in healthy eyes.

In people with dry eye, however, more Acinetobacter species were detected.

“We think the metabolites produced by these bacteria are responsible for dry eye conditions,” study coauthor Pallavi Sharma said in a news release about the findings. 

Sharma, a graduate student at Stephen F. Austin State University in Nacogdoches, Texas, presented this research last month at the annual meeting of the American Society for Biochemistry and Molecular Biology. The research team was led by Alexandra Van Kley, PhD, a professor of biology at the university.

“Once we understand the eye microbiota properly, it will improve disease diagnosis at an early stage,” Van Kley predicted in the news release. “This knowledge can also serve as a catalyst for developing innovative therapies aimed at preventing and treating ocular disease as well as those that affect the central microbiome site: The gut.”

Investigators in Australia have conducted similar experiments in patients with meibomian gland dysfunction, a condition marked by underproduction of key oils in the eye.

One group reported in August 2023 the finding of “detectable differences in the bacterial richness, diversity, and community structure of the conjunctiva and eyelid margin between individuals with meibomian gland dysfunction with and without lacrimal dysfunction, as well as to healthy controls.”

More research is needed to confirm and understand the findings, though, and “to determine if manipulating the microbiome could be a potential treatment for the condition,” they wrote.

A version of this article appeared on Medscape.com.

A mix of microbes may help explain why some people develop dry eye disease, new research showed.

This finding suggests that bacteria may cause dry eye and could someday point to new treatments for the condition and related disorders, which affect an estimated 27 million Americans, according to researchers.

Current treatments aim to preserve and enhance tears and tear production to ease the grittiness and itchiness that accompany dry eye disease. 

To examine the role of the ocular microbiome in dry eye disease, scientists in Texas analyzed swab samples from 30 men and women, nine of whom had dry eye.

They found Streptococcus and Pedobacter species were the most common bacteria in healthy eyes.

In people with dry eye, however, more Acinetobacter species were detected.

“We think the metabolites produced by these bacteria are responsible for dry eye conditions,” study coauthor Pallavi Sharma said in a news release about the findings. 

Sharma, a graduate student at Stephen F. Austin State University in Nacogdoches, Texas, presented this research last month at the annual meeting of the American Society for Biochemistry and Molecular Biology. The research team was led by Alexandra Van Kley, PhD, a professor of biology at the university.

“Once we understand the eye microbiota properly, it will improve disease diagnosis at an early stage,” Van Kley predicted in the news release. “This knowledge can also serve as a catalyst for developing innovative therapies aimed at preventing and treating ocular disease as well as those that affect the central microbiome site: The gut.”

Investigators in Australia have conducted similar experiments in patients with meibomian gland dysfunction, a condition marked by underproduction of key oils in the eye.

One group reported in August 2023 the finding of “detectable differences in the bacterial richness, diversity, and community structure of the conjunctiva and eyelid margin between individuals with meibomian gland dysfunction with and without lacrimal dysfunction, as well as to healthy controls.”

More research is needed to confirm and understand the findings, though, and “to determine if manipulating the microbiome could be a potential treatment for the condition,” they wrote.

A version of this article appeared on Medscape.com.

A mix of microbes may help explain why some people develop dry eye disease, new research showed.

This finding suggests that bacteria may cause dry eye and could someday point to new treatments for the condition and related disorders, which affect an estimated 27 million Americans, according to researchers.

Current treatments aim to preserve and enhance tears and tear production to ease the grittiness and itchiness that accompany dry eye disease. 

To examine the role of the ocular microbiome in dry eye disease, scientists in Texas analyzed swab samples from 30 men and women, nine of whom had dry eye.

They found Streptococcus and Pedobacter species were the most common bacteria in healthy eyes.

In people with dry eye, however, more Acinetobacter species were detected.

“We think the metabolites produced by these bacteria are responsible for dry eye conditions,” study coauthor Pallavi Sharma said in a news release about the findings. 

Sharma, a graduate student at Stephen F. Austin State University in Nacogdoches, Texas, presented this research last month at the annual meeting of the American Society for Biochemistry and Molecular Biology. The research team was led by Alexandra Van Kley, PhD, a professor of biology at the university.

“Once we understand the eye microbiota properly, it will improve disease diagnosis at an early stage,” Van Kley predicted in the news release. “This knowledge can also serve as a catalyst for developing innovative therapies aimed at preventing and treating ocular disease as well as those that affect the central microbiome site: The gut.”

Investigators in Australia have conducted similar experiments in patients with meibomian gland dysfunction, a condition marked by underproduction of key oils in the eye.

One group reported in August 2023 the finding of “detectable differences in the bacterial richness, diversity, and community structure of the conjunctiva and eyelid margin between individuals with meibomian gland dysfunction with and without lacrimal dysfunction, as well as to healthy controls.”

More research is needed to confirm and understand the findings, though, and “to determine if manipulating the microbiome could be a potential treatment for the condition,” they wrote.

A version of this article appeared on Medscape.com.

The acronym AIDS is redundant, loaded with stigma, and potentially harmful, according to a group of specialists who suggest replacing the term with “advanced HIV.”

The acronym AIDS has “outlived its usefulness and we should transition toward a more descriptive language that aligns with contemporary challenges in HIV,” reports Isaac Núñez, MD, from the Department of Medical Education, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City, Mexico, and colleagues.

People generally associate the acronym AIDS with patients who have no available treatment options and a short life expectancy, said Dr. Núñez. That mischaracterization may affect treatment decisions by patients and clinicians and could result in exaggerated infection-control measures.

Using the HIV/AIDS combination erroneously implies equivalence and can mislead the public and clinicians, which the authors explained in their Viewpoint article published in The Lancet HIV.
 

Original Reason for the Term

AIDS, which stands for acquired immunodeficiency syndrome, was coined in 1982 by the US Centers for Disease Control and Prevention (CDC) to name a disease with an unknown cause that affected people with weakened cell-mediated immunity.

“When HIV was found to be the cause of the disease (labeled HIV in 1986), the term AIDS, strictly speaking, became unnecessary,” Dr. Núñez said.

AIDS was originally intended as a case definition for surveillance purposes, and treatment decisions were based on whether patients met the case definition for AIDS, he pointed out.

“The fact that some people still do so in this day and age shows that this is not only unhelpful, but misleading and even harmful,” he noted. Without the label AIDS, clinicians can focus on whether and for how long people have been on treatment, whether they recently switched treatment, and other factors that will help determine appropriate care.
 

Some Organizations Removed AIDS From Their Names

Some organizations have already removed AIDS from their names. For example, the International AIDS Society–USA, which issues guidelines on antiretroviral treatment, changed its name to the International Antiviral Society–USA. 

In 2017, the name of AIDS.gov was changed to HIV.gov. In its explanation, the group wrote, “Today, people with HIV who are diagnosed early, linked to care, start antiretroviral therapy, and take it as prescribed can achieve life-long viral suppression that prevents HIV infection from progressing to AIDS.”

A different view on the term AIDS comes from Greg Millett, MPH, vice president at the Foundation for AIDS Research (amfAR) and the director of amfAR’s Public Policy Office. 

Although he believes that AIDS is an anachronistic term, as a researcher for more than 30 years in the field; a policy director in Washington; a scientist; and a person living with HIV, “it feels like a distinction without a difference. At least from where I sit, there are far more pressing issues that we’re facing as an HIV community,” Millett shared. 

For instance, “we’re seeing that global, as well as domestic, HIV funding is in, by far, the most precarious position that I’ve ever seen in the field. Calling it AIDS or HIV makes no difference in trying to alleviate that jeopardy,” he said.

Millett also said that the stigma and persecution and, in some cases, criminalization of people living with HIV or AIDS is pervasive and won’t go away with a name change, which is a point the authors also acknowledged.

“We need to focus on the social determinants of health,” he said. “That is the thing that is going to move the needle among people living with HIV, not nomenclature.”

Millett likens the argument to the one between Black and African American. “As a Black American, I remember fierce debates in the early ‘90s over whether we should be called African Americans or Blacks. Some argued that African American carried greater dignity and would help with self-esteem and address inequities by emphasizing that we are American. Many others said that it doesn’t make a difference.”

“It is clear that being called African American has not fixed intractable issues like poverty, structural racism, or inequities in incarceration,” he pointed out.
 

End the Epidemic, Not the Name 

The authors misinterpret the impact of the term on stigma, said James W. Curran, MD, MPH, dean emeritus of the Rollins School of Public Health and professor of epidemiology and global health at Emory University, both in Atlanta, Georgia. The term AIDS “is more likely attributed to the fatal nature of the infection itself,” without treatment, he explained, and the mode of transmission, exacerbated by homophobia.

“The term has been in widespread use for 40 years and recognized worldwide,” Dr. Curran, who led the nation’s efforts in the battle against HIV and AIDS at the CDC for 15 years before joining Emory as dean, said.

He also worries about the continued trajectory of lives lost: “Over 35 million people worldwide have perished from HIV/AIDS, including over 500,000 per year now.”

Meanwhile, “global programs such as PEPFAR [the US President’s Emergency Plan for AIDS Relief] are under fire and threatened by Congress as no longer necessary. Removing AIDS from the terminology may add to confusion,” making people think “that the epidemic is over,” he said.

Although the authors argue that keeping the term may cause harm, eliminating it might worsen a different kind of harm. “There is a risk that abolishing the term will further de-emphasize the importance of the problem, with no significant impact on stigma,” Dr. Curran added.

A version of this article appeared on Medscape.com.

The acronym AIDS is redundant, loaded with stigma, and potentially harmful, according to a group of specialists who suggest replacing the term with “advanced HIV.”

The acronym AIDS has “outlived its usefulness and we should transition toward a more descriptive language that aligns with contemporary challenges in HIV,” reports Isaac Núñez, MD, from the Department of Medical Education, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City, Mexico, and colleagues.

People generally associate the acronym AIDS with patients who have no available treatment options and a short life expectancy, said Dr. Núñez. That mischaracterization may affect treatment decisions by patients and clinicians and could result in exaggerated infection-control measures.

Using the HIV/AIDS combination erroneously implies equivalence and can mislead the public and clinicians, which the authors explained in their Viewpoint article published in The Lancet HIV.
 

Original Reason for the Term

AIDS, which stands for acquired immunodeficiency syndrome, was coined in 1982 by the US Centers for Disease Control and Prevention (CDC) to name a disease with an unknown cause that affected people with weakened cell-mediated immunity.

“When HIV was found to be the cause of the disease (labeled HIV in 1986), the term AIDS, strictly speaking, became unnecessary,” Dr. Núñez said.

AIDS was originally intended as a case definition for surveillance purposes, and treatment decisions were based on whether patients met the case definition for AIDS, he pointed out.

“The fact that some people still do so in this day and age shows that this is not only unhelpful, but misleading and even harmful,” he noted. Without the label AIDS, clinicians can focus on whether and for how long people have been on treatment, whether they recently switched treatment, and other factors that will help determine appropriate care.
 

Some Organizations Removed AIDS From Their Names

Some organizations have already removed AIDS from their names. For example, the International AIDS Society–USA, which issues guidelines on antiretroviral treatment, changed its name to the International Antiviral Society–USA. 

In 2017, the name of AIDS.gov was changed to HIV.gov. In its explanation, the group wrote, “Today, people with HIV who are diagnosed early, linked to care, start antiretroviral therapy, and take it as prescribed can achieve life-long viral suppression that prevents HIV infection from progressing to AIDS.”

A different view on the term AIDS comes from Greg Millett, MPH, vice president at the Foundation for AIDS Research (amfAR) and the director of amfAR’s Public Policy Office. 

Although he believes that AIDS is an anachronistic term, as a researcher for more than 30 years in the field; a policy director in Washington; a scientist; and a person living with HIV, “it feels like a distinction without a difference. At least from where I sit, there are far more pressing issues that we’re facing as an HIV community,” Millett shared. 

For instance, “we’re seeing that global, as well as domestic, HIV funding is in, by far, the most precarious position that I’ve ever seen in the field. Calling it AIDS or HIV makes no difference in trying to alleviate that jeopardy,” he said.

Millett also said that the stigma and persecution and, in some cases, criminalization of people living with HIV or AIDS is pervasive and won’t go away with a name change, which is a point the authors also acknowledged.

“We need to focus on the social determinants of health,” he said. “That is the thing that is going to move the needle among people living with HIV, not nomenclature.”

Millett likens the argument to the one between Black and African American. “As a Black American, I remember fierce debates in the early ‘90s over whether we should be called African Americans or Blacks. Some argued that African American carried greater dignity and would help with self-esteem and address inequities by emphasizing that we are American. Many others said that it doesn’t make a difference.”

“It is clear that being called African American has not fixed intractable issues like poverty, structural racism, or inequities in incarceration,” he pointed out.
 

End the Epidemic, Not the Name 

The authors misinterpret the impact of the term on stigma, said James W. Curran, MD, MPH, dean emeritus of the Rollins School of Public Health and professor of epidemiology and global health at Emory University, both in Atlanta, Georgia. The term AIDS “is more likely attributed to the fatal nature of the infection itself,” without treatment, he explained, and the mode of transmission, exacerbated by homophobia.

“The term has been in widespread use for 40 years and recognized worldwide,” Dr. Curran, who led the nation’s efforts in the battle against HIV and AIDS at the CDC for 15 years before joining Emory as dean, said.

He also worries about the continued trajectory of lives lost: “Over 35 million people worldwide have perished from HIV/AIDS, including over 500,000 per year now.”

Meanwhile, “global programs such as PEPFAR [the US President’s Emergency Plan for AIDS Relief] are under fire and threatened by Congress as no longer necessary. Removing AIDS from the terminology may add to confusion,” making people think “that the epidemic is over,” he said.

Although the authors argue that keeping the term may cause harm, eliminating it might worsen a different kind of harm. “There is a risk that abolishing the term will further de-emphasize the importance of the problem, with no significant impact on stigma,” Dr. Curran added.

A version of this article appeared on Medscape.com.

The acronym AIDS is redundant, loaded with stigma, and potentially harmful, according to a group of specialists who suggest replacing the term with “advanced HIV.”

The acronym AIDS has “outlived its usefulness and we should transition toward a more descriptive language that aligns with contemporary challenges in HIV,” reports Isaac Núñez, MD, from the Department of Medical Education, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City, Mexico, and colleagues.

People generally associate the acronym AIDS with patients who have no available treatment options and a short life expectancy, said Dr. Núñez. That mischaracterization may affect treatment decisions by patients and clinicians and could result in exaggerated infection-control measures.

Using the HIV/AIDS combination erroneously implies equivalence and can mislead the public and clinicians, which the authors explained in their Viewpoint article published in The Lancet HIV.
 

Original Reason for the Term

AIDS, which stands for acquired immunodeficiency syndrome, was coined in 1982 by the US Centers for Disease Control and Prevention (CDC) to name a disease with an unknown cause that affected people with weakened cell-mediated immunity.

“When HIV was found to be the cause of the disease (labeled HIV in 1986), the term AIDS, strictly speaking, became unnecessary,” Dr. Núñez said.

AIDS was originally intended as a case definition for surveillance purposes, and treatment decisions were based on whether patients met the case definition for AIDS, he pointed out.

“The fact that some people still do so in this day and age shows that this is not only unhelpful, but misleading and even harmful,” he noted. Without the label AIDS, clinicians can focus on whether and for how long people have been on treatment, whether they recently switched treatment, and other factors that will help determine appropriate care.
 

Some Organizations Removed AIDS From Their Names

Some organizations have already removed AIDS from their names. For example, the International AIDS Society–USA, which issues guidelines on antiretroviral treatment, changed its name to the International Antiviral Society–USA. 

In 2017, the name of AIDS.gov was changed to HIV.gov. In its explanation, the group wrote, “Today, people with HIV who are diagnosed early, linked to care, start antiretroviral therapy, and take it as prescribed can achieve life-long viral suppression that prevents HIV infection from progressing to AIDS.”

A different view on the term AIDS comes from Greg Millett, MPH, vice president at the Foundation for AIDS Research (amfAR) and the director of amfAR’s Public Policy Office. 

Although he believes that AIDS is an anachronistic term, as a researcher for more than 30 years in the field; a policy director in Washington; a scientist; and a person living with HIV, “it feels like a distinction without a difference. At least from where I sit, there are far more pressing issues that we’re facing as an HIV community,” Millett shared. 

For instance, “we’re seeing that global, as well as domestic, HIV funding is in, by far, the most precarious position that I’ve ever seen in the field. Calling it AIDS or HIV makes no difference in trying to alleviate that jeopardy,” he said.

Millett also said that the stigma and persecution and, in some cases, criminalization of people living with HIV or AIDS is pervasive and won’t go away with a name change, which is a point the authors also acknowledged.

“We need to focus on the social determinants of health,” he said. “That is the thing that is going to move the needle among people living with HIV, not nomenclature.”

Millett likens the argument to the one between Black and African American. “As a Black American, I remember fierce debates in the early ‘90s over whether we should be called African Americans or Blacks. Some argued that African American carried greater dignity and would help with self-esteem and address inequities by emphasizing that we are American. Many others said that it doesn’t make a difference.”

“It is clear that being called African American has not fixed intractable issues like poverty, structural racism, or inequities in incarceration,” he pointed out.
 

End the Epidemic, Not the Name 

The authors misinterpret the impact of the term on stigma, said James W. Curran, MD, MPH, dean emeritus of the Rollins School of Public Health and professor of epidemiology and global health at Emory University, both in Atlanta, Georgia. The term AIDS “is more likely attributed to the fatal nature of the infection itself,” without treatment, he explained, and the mode of transmission, exacerbated by homophobia.

“The term has been in widespread use for 40 years and recognized worldwide,” Dr. Curran, who led the nation’s efforts in the battle against HIV and AIDS at the CDC for 15 years before joining Emory as dean, said.

He also worries about the continued trajectory of lives lost: “Over 35 million people worldwide have perished from HIV/AIDS, including over 500,000 per year now.”

Meanwhile, “global programs such as PEPFAR [the US President’s Emergency Plan for AIDS Relief] are under fire and threatened by Congress as no longer necessary. Removing AIDS from the terminology may add to confusion,” making people think “that the epidemic is over,” he said.

Although the authors argue that keeping the term may cause harm, eliminating it might worsen a different kind of harm. “There is a risk that abolishing the term will further de-emphasize the importance of the problem, with no significant impact on stigma,” Dr. Curran added.

A version of this article appeared on Medscape.com.

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Dou_Diana_CA_web.jpg

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

Anguera_Montserrat_PA_web.jpg

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

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“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Darrah_Erika_MD_web.jpg

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

Plath_Kathrin_CA_web.jpg

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Dou_Diana_CA_web.jpg

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

Anguera_Montserrat_PA_web.jpg

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

167534_photo_web.jpg

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Darrah_Erika_MD_web.jpg

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

Plath_Kathrin_CA_web.jpg

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Dou_Diana_CA_web.jpg

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

Anguera_Montserrat_PA_web.jpg

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

167534_photo_web.jpg

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Darrah_Erika_MD_web.jpg

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

Plath_Kathrin_CA_web.jpg

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

TOPLINE:

Hospitalization for influenza is linked to a greater risk for subsequent neurologic disorders including migraine, stroke, or epilepsy than is hospitalization for COVID-19, results of a large study show.

METHODOLOGY:

• Researchers used healthcare claims data to compare 77,300 people hospitalized with COVID-19 with 77,300 hospitalized with influenza. The study did not include individuals with long COVID.
• In the final sample of 154,500 participants, the mean age was 51 years, and more than half (58%) were female.
• Investigators followed participants from both cohorts for a year to find out how many of them had medical care for six of the most common neurologic disorders: migraine, epilepsy, stroke, neuropathy, movement disorders, and dementia.
• If participants had one of these neurologic disorders prior to the original hospitalization, the primary outcome involved subsequent healthcare encounters for the neurologic diagnosis.

TAKEAWAY:

• Participants hospitalized with COVID-19 versus influenza were significantly less likely to require care in the following year for migraine (2% vs 3.2%), epilepsy (1.6% vs 2.1%), neuropathy (1.9% vs 3.6%), movement disorders (1.5% vs 2.5%), stroke (2% vs 2.4%), and dementia (2% vs 2.3%) (all P < .001).
• After adjusting for age, sex, and other health conditions, researchers found that people hospitalized with COVID-19 had a 35% lower risk of receiving care for migraine, a 22% lower risk of receiving care for epilepsy, and a 44% lower risk of receiving care for neuropathy than those with influenza. They also had a 36% lower risk of receiving care for movement disorders, a 10% lower risk for stroke (all P < .001), as well as a 7% lower risk for dementia (P = .0007).
• In participants who did not have a preexisting neurologic condition at the time of hospitalization for either COVID-19 or influenza, 2.8% hospitalized with COVID-19 developed one in the next year compared with 5% of those hospitalized with influenza.

IN PRACTICE:

“While the results were not what we expected to find, they are reassuring in that we found being hospitalized with COVID did not lead to more care for common neurologic conditions when compared to being hospitalized with influenza,” study investigator Brian C. Callaghan, MD, of University of Michigan, Ann Arbor, said in a press release.

SOURCE:

Adam de Havenon, MD, of Yale University in New Haven, Connecticut, led the study, which was published online on March 20 in Neurology.

LIMITATIONS:

The study relied on ICD codes in health claims databases, which could introduce misclassification bias. Also, by selecting only individuals who had associated hospital-based care, there may have been a selection bias based on disease severity.

DISCLOSURES:

The study was funded by the American Academy of Neurology. Dr. De Havenon reported receiving consultant fees from Integra and Novo Nordisk and royalty fees from UpToDate and has equity in Titin KM and Certus. Dr. Callaghan has consulted for DynaMed and the Vaccine Injury Compensation Program. Other disclosures were noted in the original article.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Hospitalization for influenza is linked to a greater risk for subsequent neurologic disorders including migraine, stroke, or epilepsy than is hospitalization for COVID-19, results of a large study show.

METHODOLOGY:

• Researchers used healthcare claims data to compare 77,300 people hospitalized with COVID-19 with 77,300 hospitalized with influenza. The study did not include individuals with long COVID.
• In the final sample of 154,500 participants, the mean age was 51 years, and more than half (58%) were female.
• Investigators followed participants from both cohorts for a year to find out how many of them had medical care for six of the most common neurologic disorders: migraine, epilepsy, stroke, neuropathy, movement disorders, and dementia.
• If participants had one of these neurologic disorders prior to the original hospitalization, the primary outcome involved subsequent healthcare encounters for the neurologic diagnosis.

TAKEAWAY:

• Participants hospitalized with COVID-19 versus influenza were significantly less likely to require care in the following year for migraine (2% vs 3.2%), epilepsy (1.6% vs 2.1%), neuropathy (1.9% vs 3.6%), movement disorders (1.5% vs 2.5%), stroke (2% vs 2.4%), and dementia (2% vs 2.3%) (all P < .001).
• After adjusting for age, sex, and other health conditions, researchers found that people hospitalized with COVID-19 had a 35% lower risk of receiving care for migraine, a 22% lower risk of receiving care for epilepsy, and a 44% lower risk of receiving care for neuropathy than those with influenza. They also had a 36% lower risk of receiving care for movement disorders, a 10% lower risk for stroke (all P < .001), as well as a 7% lower risk for dementia (P = .0007).
• In participants who did not have a preexisting neurologic condition at the time of hospitalization for either COVID-19 or influenza, 2.8% hospitalized with COVID-19 developed one in the next year compared with 5% of those hospitalized with influenza.

IN PRACTICE:

“While the results were not what we expected to find, they are reassuring in that we found being hospitalized with COVID did not lead to more care for common neurologic conditions when compared to being hospitalized with influenza,” study investigator Brian C. Callaghan, MD, of University of Michigan, Ann Arbor, said in a press release.

SOURCE:

Adam de Havenon, MD, of Yale University in New Haven, Connecticut, led the study, which was published online on March 20 in Neurology.

LIMITATIONS:

The study relied on ICD codes in health claims databases, which could introduce misclassification bias. Also, by selecting only individuals who had associated hospital-based care, there may have been a selection bias based on disease severity.

DISCLOSURES:

The study was funded by the American Academy of Neurology. Dr. De Havenon reported receiving consultant fees from Integra and Novo Nordisk and royalty fees from UpToDate and has equity in Titin KM and Certus. Dr. Callaghan has consulted for DynaMed and the Vaccine Injury Compensation Program. Other disclosures were noted in the original article.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Hospitalization for influenza is linked to a greater risk for subsequent neurologic disorders including migraine, stroke, or epilepsy than is hospitalization for COVID-19, results of a large study show.

METHODOLOGY:

• Researchers used healthcare claims data to compare 77,300 people hospitalized with COVID-19 with 77,300 hospitalized with influenza. The study did not include individuals with long COVID.
• In the final sample of 154,500 participants, the mean age was 51 years, and more than half (58%) were female.
• Investigators followed participants from both cohorts for a year to find out how many of them had medical care for six of the most common neurologic disorders: migraine, epilepsy, stroke, neuropathy, movement disorders, and dementia.
• If participants had one of these neurologic disorders prior to the original hospitalization, the primary outcome involved subsequent healthcare encounters for the neurologic diagnosis.

TAKEAWAY:

• Participants hospitalized with COVID-19 versus influenza were significantly less likely to require care in the following year for migraine (2% vs 3.2%), epilepsy (1.6% vs 2.1%), neuropathy (1.9% vs 3.6%), movement disorders (1.5% vs 2.5%), stroke (2% vs 2.4%), and dementia (2% vs 2.3%) (all P < .001).
• After adjusting for age, sex, and other health conditions, researchers found that people hospitalized with COVID-19 had a 35% lower risk of receiving care for migraine, a 22% lower risk of receiving care for epilepsy, and a 44% lower risk of receiving care for neuropathy than those with influenza. They also had a 36% lower risk of receiving care for movement disorders, a 10% lower risk for stroke (all P < .001), as well as a 7% lower risk for dementia (P = .0007).
• In participants who did not have a preexisting neurologic condition at the time of hospitalization for either COVID-19 or influenza, 2.8% hospitalized with COVID-19 developed one in the next year compared with 5% of those hospitalized with influenza.

IN PRACTICE:

“While the results were not what we expected to find, they are reassuring in that we found being hospitalized with COVID did not lead to more care for common neurologic conditions when compared to being hospitalized with influenza,” study investigator Brian C. Callaghan, MD, of University of Michigan, Ann Arbor, said in a press release.

SOURCE:

Adam de Havenon, MD, of Yale University in New Haven, Connecticut, led the study, which was published online on March 20 in Neurology.

LIMITATIONS:

The study relied on ICD codes in health claims databases, which could introduce misclassification bias. Also, by selecting only individuals who had associated hospital-based care, there may have been a selection bias based on disease severity.

DISCLOSURES:

The study was funded by the American Academy of Neurology. Dr. De Havenon reported receiving consultant fees from Integra and Novo Nordisk and royalty fees from UpToDate and has equity in Titin KM and Certus. Dr. Callaghan has consulted for DynaMed and the Vaccine Injury Compensation Program. Other disclosures were noted in the original article.
 

A version of this article appeared on Medscape.com.

Sublingual immunotherapy (SLIT) is as safe and effective for high-risk older children and adolescents as oral immunotherapy (OIT) is for infants and preschoolers, according to new research.

Preliminary data from a study of more than 180 pediatric patients with multiple food allergies showed that while most patients had mild symptoms, none experienced a severe grade 4 reaction during the buildup and maintenance phase of SLIT.

In addition, 70% of those tested at the end of the treatment protocol were able to tolerate 300 mg of their allergen, a success rate nearly as high as that for OIT.

The study was published in The Journal of Allergy and Clinical Immunology: In Practice.

SLIT has been used successfully in the treatment of environmental allergens such as grass and tree pollen and dust mites. In this study, researchers decided to test SLIT’s effectiveness and safety in the treatment of food allergies in older children.

“We knew that OIT is very effective and safe in infants and toddlers, but there was literature illustrating that for older, school-age kids and adolescents, OIT is not safe enough, as those older age groups tend to have higher risk of severe reaction during treatment,” senior author Edmond Chan, MD, clinical professor of allergy at the University of British Columbia and pediatric allergist at BC Children’s Hospital, both in Vancouver, British Columbia, Canada, told this news organization. “With that knowledge, we decided to explore SLIT as another first-phase therapy for the older kids.”

The investigators recruited 188 high-risk older children aged 4-18 years for multifood SLIT. Most (61.7%) participants had multiple food allergies. Approximately 68% were male, and the population’s median age was 11.3 years.

Nearly half (48.4%) of participants had atopic dermatitis, 45.2% had asthma, 58.0% had allergic rhinitis, and 2.66% had preexisting eosinophilic esophagitis.

Most (75.0%) of the children were classified as higher risk, and 23 had a history of a grade 3 or 4 reaction before beginning SLIT.

Of the 188 children who were initially enrolled in the study, 173 (92.0%) finished their SLIT buildup phase.

Because the study started when COVID-19 pandemic restrictions were in place, the SLIT protocol mandated that patients be seen virtually. The patients’ caregivers learned how to mix and administer the required doses at home using recipes specially developed by the research team that used products bought at the grocery store.

A wide variety of food allergens were treated, including peanut, other legumes, tree nuts, sesame, other seeds, egg, cow’s milk, fish, wheat, shrimp, and other allergens.

The children built up to 2-mg protein SLIT maintenance over the course of three to five visits under nurse supervision.

After 1-2 years of daily SLIT maintenance, patients were offered a low-dose oral food challenge (OFC; cumulative dose: 300 mg of protein) with the goal of bypassing OIT buildup.

Nearly all patients (93.1%) had symptoms during SLIT buildup, but most were mild grade 1 (52.1%) or 2 (40.4%) reactions. Only one patient had a grade 3 reaction. None of the patients experienced a severe grade 4 reaction.

The most common grade 1 reaction was oral itch, an expected symptom of SLIT, which occurred in 82.7% of the patients.

Four patients (2.10%) received epinephrine during buildup and went to the emergency department. All these patients returned to continue SLIT without further need for epinephrine.

To test the effectiveness of SLIT, the researchers performed 50 low-dose OFCs in 20 patients. Of these food challenges, 35 (70%) were successful, and patients were asked to start daily 300-mg OIT maintenance, thus bypassing OIT buildup.

An additional nine OFCs that were unsuccessful were counseled to self-escalate from 80 mg or higher to 300 mg at home with medical guidance as needed.

“Our preliminary data of 20 patients and 50 low-dose oral food challenges suggest that an initial phase of 1-2 years of 2-mg daily SLIT therapy may be a safe and effective way to bypass the OIT buildup phase without the need for dozens of in-person visits with an allergist,” said Dr. Chan.

“So now we have the best of both worlds. We harness the safety of SLIT for the first 1-2 years, with the effectiveness of OIT for the remainder of the treatment period,” he said.
 

Adds to Evidence

Commenting on the study for this news organization, Julia Upton, MD, associate professor of pediatrics at the University of Toronto, Toronto, Ontario, Canada, said, “This study adds to the evidence that consistent, low exposure to food drives meaningful desensitization far above the daily dose.” Upton did not participate in the research.

“Prior prospective studies in SLIT demonstrated that small single-digit-milligram doses and time greatly increased the threshold of reaction. This real-world report suggests that a way to utilize that threshold increase is by switching to a commonly used maintenance dose of OIT,” said Dr. Upton.

“Although few patients have been assessed for the 300-mg challenge, this study is notable for the age group of 4-18 years, and that many of the patients had reacted to low doses in the past. It also shows that many families are capable of diluting and mixing their own immunotherapy solutions with store-bought foods under the guidance of an experienced allergy clinic,” she added.

“Overall, evidence is building that by various routes, initial small amounts with minimal updoses, plus the tincture of time, may be preferred to multiple frequent updosing from multiple perspectives, including safety, feasibility, cost, and medical resources. It will also be important to understand the preferences and goals of the patient and family as various regimens become more available,” Dr. Upton concluded.

The study was funded by BC Children’s Hospital Foundation. Dr. Chan reported receiving research support from DVB Technologies; has been a member of advisory boards for Pfizer, Miravo, Medexus, Leo Pharma, Kaleo, DBV, AllerGenis, Sanofi, Genzyme, Bausch Health, Avir Pharma, AstraZeneca, ALK, and Alladapt; and was a colead of the CSACI OIT guidelines. Dr. Upton reported research support/grants from Novartis, Regeneron, Sanofi, ALK Abello, DBV Technologies, CIHR, and SickKids Food Allergy and Anaphylaxis Program and fees from Pfizer, ALK Abello, Bausch Health, Astra Zeneca, and Pharming. She serves as an associate editor for Allergy, Asthma & Clinical Immunology and is on the Board of Directors of Canadian Society of Allergy and Clinical Immunology and the Healthcare Advisory Board of Food Allergy Canada.

A version of this article appeared on Medscape.com .

Sublingual immunotherapy (SLIT) is as safe and effective for high-risk older children and adolescents as oral immunotherapy (OIT) is for infants and preschoolers, according to new research.

Preliminary data from a study of more than 180 pediatric patients with multiple food allergies showed that while most patients had mild symptoms, none experienced a severe grade 4 reaction during the buildup and maintenance phase of SLIT.

In addition, 70% of those tested at the end of the treatment protocol were able to tolerate 300 mg of their allergen, a success rate nearly as high as that for OIT.

The study was published in The Journal of Allergy and Clinical Immunology: In Practice.

SLIT has been used successfully in the treatment of environmental allergens such as grass and tree pollen and dust mites. In this study, researchers decided to test SLIT’s effectiveness and safety in the treatment of food allergies in older children.

“We knew that OIT is very effective and safe in infants and toddlers, but there was literature illustrating that for older, school-age kids and adolescents, OIT is not safe enough, as those older age groups tend to have higher risk of severe reaction during treatment,” senior author Edmond Chan, MD, clinical professor of allergy at the University of British Columbia and pediatric allergist at BC Children’s Hospital, both in Vancouver, British Columbia, Canada, told this news organization. “With that knowledge, we decided to explore SLIT as another first-phase therapy for the older kids.”

The investigators recruited 188 high-risk older children aged 4-18 years for multifood SLIT. Most (61.7%) participants had multiple food allergies. Approximately 68% were male, and the population’s median age was 11.3 years.

Nearly half (48.4%) of participants had atopic dermatitis, 45.2% had asthma, 58.0% had allergic rhinitis, and 2.66% had preexisting eosinophilic esophagitis.

Most (75.0%) of the children were classified as higher risk, and 23 had a history of a grade 3 or 4 reaction before beginning SLIT.

Of the 188 children who were initially enrolled in the study, 173 (92.0%) finished their SLIT buildup phase.

Because the study started when COVID-19 pandemic restrictions were in place, the SLIT protocol mandated that patients be seen virtually. The patients’ caregivers learned how to mix and administer the required doses at home using recipes specially developed by the research team that used products bought at the grocery store.

A wide variety of food allergens were treated, including peanut, other legumes, tree nuts, sesame, other seeds, egg, cow’s milk, fish, wheat, shrimp, and other allergens.

The children built up to 2-mg protein SLIT maintenance over the course of three to five visits under nurse supervision.

After 1-2 years of daily SLIT maintenance, patients were offered a low-dose oral food challenge (OFC; cumulative dose: 300 mg of protein) with the goal of bypassing OIT buildup.

Nearly all patients (93.1%) had symptoms during SLIT buildup, but most were mild grade 1 (52.1%) or 2 (40.4%) reactions. Only one patient had a grade 3 reaction. None of the patients experienced a severe grade 4 reaction.

The most common grade 1 reaction was oral itch, an expected symptom of SLIT, which occurred in 82.7% of the patients.

Four patients (2.10%) received epinephrine during buildup and went to the emergency department. All these patients returned to continue SLIT without further need for epinephrine.

To test the effectiveness of SLIT, the researchers performed 50 low-dose OFCs in 20 patients. Of these food challenges, 35 (70%) were successful, and patients were asked to start daily 300-mg OIT maintenance, thus bypassing OIT buildup.

An additional nine OFCs that were unsuccessful were counseled to self-escalate from 80 mg or higher to 300 mg at home with medical guidance as needed.

“Our preliminary data of 20 patients and 50 low-dose oral food challenges suggest that an initial phase of 1-2 years of 2-mg daily SLIT therapy may be a safe and effective way to bypass the OIT buildup phase without the need for dozens of in-person visits with an allergist,” said Dr. Chan.

“So now we have the best of both worlds. We harness the safety of SLIT for the first 1-2 years, with the effectiveness of OIT for the remainder of the treatment period,” he said.
 

Adds to Evidence

Commenting on the study for this news organization, Julia Upton, MD, associate professor of pediatrics at the University of Toronto, Toronto, Ontario, Canada, said, “This study adds to the evidence that consistent, low exposure to food drives meaningful desensitization far above the daily dose.” Upton did not participate in the research.

“Prior prospective studies in SLIT demonstrated that small single-digit-milligram doses and time greatly increased the threshold of reaction. This real-world report suggests that a way to utilize that threshold increase is by switching to a commonly used maintenance dose of OIT,” said Dr. Upton.

“Although few patients have been assessed for the 300-mg challenge, this study is notable for the age group of 4-18 years, and that many of the patients had reacted to low doses in the past. It also shows that many families are capable of diluting and mixing their own immunotherapy solutions with store-bought foods under the guidance of an experienced allergy clinic,” she added.

“Overall, evidence is building that by various routes, initial small amounts with minimal updoses, plus the tincture of time, may be preferred to multiple frequent updosing from multiple perspectives, including safety, feasibility, cost, and medical resources. It will also be important to understand the preferences and goals of the patient and family as various regimens become more available,” Dr. Upton concluded.

The study was funded by BC Children’s Hospital Foundation. Dr. Chan reported receiving research support from DVB Technologies; has been a member of advisory boards for Pfizer, Miravo, Medexus, Leo Pharma, Kaleo, DBV, AllerGenis, Sanofi, Genzyme, Bausch Health, Avir Pharma, AstraZeneca, ALK, and Alladapt; and was a colead of the CSACI OIT guidelines. Dr. Upton reported research support/grants from Novartis, Regeneron, Sanofi, ALK Abello, DBV Technologies, CIHR, and SickKids Food Allergy and Anaphylaxis Program and fees from Pfizer, ALK Abello, Bausch Health, Astra Zeneca, and Pharming. She serves as an associate editor for Allergy, Asthma & Clinical Immunology and is on the Board of Directors of Canadian Society of Allergy and Clinical Immunology and the Healthcare Advisory Board of Food Allergy Canada.

A version of this article appeared on Medscape.com .

Sublingual immunotherapy (SLIT) is as safe and effective for high-risk older children and adolescents as oral immunotherapy (OIT) is for infants and preschoolers, according to new research.

Preliminary data from a study of more than 180 pediatric patients with multiple food allergies showed that while most patients had mild symptoms, none experienced a severe grade 4 reaction during the buildup and maintenance phase of SLIT.

In addition, 70% of those tested at the end of the treatment protocol were able to tolerate 300 mg of their allergen, a success rate nearly as high as that for OIT.

The study was published in The Journal of Allergy and Clinical Immunology: In Practice.

SLIT has been used successfully in the treatment of environmental allergens such as grass and tree pollen and dust mites. In this study, researchers decided to test SLIT’s effectiveness and safety in the treatment of food allergies in older children.

“We knew that OIT is very effective and safe in infants and toddlers, but there was literature illustrating that for older, school-age kids and adolescents, OIT is not safe enough, as those older age groups tend to have higher risk of severe reaction during treatment,” senior author Edmond Chan, MD, clinical professor of allergy at the University of British Columbia and pediatric allergist at BC Children’s Hospital, both in Vancouver, British Columbia, Canada, told this news organization. “With that knowledge, we decided to explore SLIT as another first-phase therapy for the older kids.”

The investigators recruited 188 high-risk older children aged 4-18 years for multifood SLIT. Most (61.7%) participants had multiple food allergies. Approximately 68% were male, and the population’s median age was 11.3 years.

Nearly half (48.4%) of participants had atopic dermatitis, 45.2% had asthma, 58.0% had allergic rhinitis, and 2.66% had preexisting eosinophilic esophagitis.

Most (75.0%) of the children were classified as higher risk, and 23 had a history of a grade 3 or 4 reaction before beginning SLIT.

Of the 188 children who were initially enrolled in the study, 173 (92.0%) finished their SLIT buildup phase.

Because the study started when COVID-19 pandemic restrictions were in place, the SLIT protocol mandated that patients be seen virtually. The patients’ caregivers learned how to mix and administer the required doses at home using recipes specially developed by the research team that used products bought at the grocery store.

A wide variety of food allergens were treated, including peanut, other legumes, tree nuts, sesame, other seeds, egg, cow’s milk, fish, wheat, shrimp, and other allergens.

The children built up to 2-mg protein SLIT maintenance over the course of three to five visits under nurse supervision.

After 1-2 years of daily SLIT maintenance, patients were offered a low-dose oral food challenge (OFC; cumulative dose: 300 mg of protein) with the goal of bypassing OIT buildup.

Nearly all patients (93.1%) had symptoms during SLIT buildup, but most were mild grade 1 (52.1%) or 2 (40.4%) reactions. Only one patient had a grade 3 reaction. None of the patients experienced a severe grade 4 reaction.

The most common grade 1 reaction was oral itch, an expected symptom of SLIT, which occurred in 82.7% of the patients.

Four patients (2.10%) received epinephrine during buildup and went to the emergency department. All these patients returned to continue SLIT without further need for epinephrine.

To test the effectiveness of SLIT, the researchers performed 50 low-dose OFCs in 20 patients. Of these food challenges, 35 (70%) were successful, and patients were asked to start daily 300-mg OIT maintenance, thus bypassing OIT buildup.

An additional nine OFCs that were unsuccessful were counseled to self-escalate from 80 mg or higher to 300 mg at home with medical guidance as needed.

“Our preliminary data of 20 patients and 50 low-dose oral food challenges suggest that an initial phase of 1-2 years of 2-mg daily SLIT therapy may be a safe and effective way to bypass the OIT buildup phase without the need for dozens of in-person visits with an allergist,” said Dr. Chan.

“So now we have the best of both worlds. We harness the safety of SLIT for the first 1-2 years, with the effectiveness of OIT for the remainder of the treatment period,” he said.
 

Adds to Evidence

Commenting on the study for this news organization, Julia Upton, MD, associate professor of pediatrics at the University of Toronto, Toronto, Ontario, Canada, said, “This study adds to the evidence that consistent, low exposure to food drives meaningful desensitization far above the daily dose.” Upton did not participate in the research.

“Prior prospective studies in SLIT demonstrated that small single-digit-milligram doses and time greatly increased the threshold of reaction. This real-world report suggests that a way to utilize that threshold increase is by switching to a commonly used maintenance dose of OIT,” said Dr. Upton.

“Although few patients have been assessed for the 300-mg challenge, this study is notable for the age group of 4-18 years, and that many of the patients had reacted to low doses in the past. It also shows that many families are capable of diluting and mixing their own immunotherapy solutions with store-bought foods under the guidance of an experienced allergy clinic,” she added.

“Overall, evidence is building that by various routes, initial small amounts with minimal updoses, plus the tincture of time, may be preferred to multiple frequent updosing from multiple perspectives, including safety, feasibility, cost, and medical resources. It will also be important to understand the preferences and goals of the patient and family as various regimens become more available,” Dr. Upton concluded.

The study was funded by BC Children’s Hospital Foundation. Dr. Chan reported receiving research support from DVB Technologies; has been a member of advisory boards for Pfizer, Miravo, Medexus, Leo Pharma, Kaleo, DBV, AllerGenis, Sanofi, Genzyme, Bausch Health, Avir Pharma, AstraZeneca, ALK, and Alladapt; and was a colead of the CSACI OIT guidelines. Dr. Upton reported research support/grants from Novartis, Regeneron, Sanofi, ALK Abello, DBV Technologies, CIHR, and SickKids Food Allergy and Anaphylaxis Program and fees from Pfizer, ALK Abello, Bausch Health, Astra Zeneca, and Pharming. She serves as an associate editor for Allergy, Asthma & Clinical Immunology and is on the Board of Directors of Canadian Society of Allergy and Clinical Immunology and the Healthcare Advisory Board of Food Allergy Canada.

A version of this article appeared on Medscape.com .

When the world needed a COVID vaccine, leading HIV investigators answered the call to intervene in the coronavirus pandemic. Now, efforts to discover the world’s first HIV vaccine are revitalized.

“The body is capable of making antibodies to protect us from HIV,” says Yunda Huang, PhD, from the Fred Hutchinson Cancer Center in Seattle, Washington, who sat down with me before her talk today at the Conference on Retroviruses & Opportunistic Infections.

Dr. Huang spoke about the path forward for neutralizing antibody protection after the last attempt in a generation of HIV vaccine development ended in disappointment.

The past two decades marked the rise in HIV broadly neutralizing antibodies, with vaccine strategies to induce them. Promising advances include germline approaches, mRNA, and nanoparticle technologies.

The PrEP vaccine trial testing two experimental prevention regimens in Africa was stopped after investigators reported there is “little to no chance” the trial will show the vaccines are effective.
 

A Shape-Shifting Virus

HIV has been called the shape-shifting virus because it disguises itself so that even when people are able to make antibodies to it, the virus changes to escape.

But Dr. Huang and others are optimistic that an effective vaccine is still possible.

“We cannot and will not lose hope that the world will have an effective HIV vaccine that is accessible by all who need it, anywhere,” International AIDS Society (IAS) Executive Director Birgit Poniatowski said in a statement in December, when the trial was stopped.

HIV is a still persistent problem in the United States, according to the Centers for Disease Control and Prevention that reports it has affected an estimated 1.2 million people.

With new people infected every day around the globe, Dr. Huang says she feels a sense of urgency to help. “I think about all the people around the globe and the large number of young girls being hurt and I know our big pool of talent can intervene to change what we see happening.” 

Dr. Huang says the clinical trial failures we’ve seen so far will help guide next steps in HIV research as much as successes typically do.
 

Advances in the Field

With significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, a new wave of clinical trials are on the way.

And with so many new approaches in the works, the HIV Vaccine Trials Network is retooling how it operates to navigate a burgeoning field and identify the most promising regimens.

A new Discovery Medicine Program will help the network assess new vaccine candidates. It will also aim to rule out others earlier on.

For COVID-19 and the flu, multimeric nanoparticles are an important alternative under investigation that could also be adapted for HIV.

Dr. Huang says she is particularly excited to watch the progress in cocktails of combination monoclonals. “I’ve been working in this field for 20 years now and there is a misconception that with pre-exposure prophylaxis, our job is done, but HIV is so far from away from being solved.”

But you just never know, Dr. Huang says. With new research, “we could bump on something at any point that changes everything.”

A version of this article appeared on Medscape.com.

When the world needed a COVID vaccine, leading HIV investigators answered the call to intervene in the coronavirus pandemic. Now, efforts to discover the world’s first HIV vaccine are revitalized.

“The body is capable of making antibodies to protect us from HIV,” says Yunda Huang, PhD, from the Fred Hutchinson Cancer Center in Seattle, Washington, who sat down with me before her talk today at the Conference on Retroviruses & Opportunistic Infections.

Dr. Huang spoke about the path forward for neutralizing antibody protection after the last attempt in a generation of HIV vaccine development ended in disappointment.

The past two decades marked the rise in HIV broadly neutralizing antibodies, with vaccine strategies to induce them. Promising advances include germline approaches, mRNA, and nanoparticle technologies.

The PrEP vaccine trial testing two experimental prevention regimens in Africa was stopped after investigators reported there is “little to no chance” the trial will show the vaccines are effective.
 

A Shape-Shifting Virus

HIV has been called the shape-shifting virus because it disguises itself so that even when people are able to make antibodies to it, the virus changes to escape.

But Dr. Huang and others are optimistic that an effective vaccine is still possible.

“We cannot and will not lose hope that the world will have an effective HIV vaccine that is accessible by all who need it, anywhere,” International AIDS Society (IAS) Executive Director Birgit Poniatowski said in a statement in December, when the trial was stopped.

HIV is a still persistent problem in the United States, according to the Centers for Disease Control and Prevention that reports it has affected an estimated 1.2 million people.

With new people infected every day around the globe, Dr. Huang says she feels a sense of urgency to help. “I think about all the people around the globe and the large number of young girls being hurt and I know our big pool of talent can intervene to change what we see happening.” 

Dr. Huang says the clinical trial failures we’ve seen so far will help guide next steps in HIV research as much as successes typically do.
 

Advances in the Field

With significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, a new wave of clinical trials are on the way.

And with so many new approaches in the works, the HIV Vaccine Trials Network is retooling how it operates to navigate a burgeoning field and identify the most promising regimens.

A new Discovery Medicine Program will help the network assess new vaccine candidates. It will also aim to rule out others earlier on.

For COVID-19 and the flu, multimeric nanoparticles are an important alternative under investigation that could also be adapted for HIV.

Dr. Huang says she is particularly excited to watch the progress in cocktails of combination monoclonals. “I’ve been working in this field for 20 years now and there is a misconception that with pre-exposure prophylaxis, our job is done, but HIV is so far from away from being solved.”

But you just never know, Dr. Huang says. With new research, “we could bump on something at any point that changes everything.”

A version of this article appeared on Medscape.com.

When the world needed a COVID vaccine, leading HIV investigators answered the call to intervene in the coronavirus pandemic. Now, efforts to discover the world’s first HIV vaccine are revitalized.

“The body is capable of making antibodies to protect us from HIV,” says Yunda Huang, PhD, from the Fred Hutchinson Cancer Center in Seattle, Washington, who sat down with me before her talk today at the Conference on Retroviruses & Opportunistic Infections.

Dr. Huang spoke about the path forward for neutralizing antibody protection after the last attempt in a generation of HIV vaccine development ended in disappointment.

The past two decades marked the rise in HIV broadly neutralizing antibodies, with vaccine strategies to induce them. Promising advances include germline approaches, mRNA, and nanoparticle technologies.

The PrEP vaccine trial testing two experimental prevention regimens in Africa was stopped after investigators reported there is “little to no chance” the trial will show the vaccines are effective.
 

A Shape-Shifting Virus

HIV has been called the shape-shifting virus because it disguises itself so that even when people are able to make antibodies to it, the virus changes to escape.

But Dr. Huang and others are optimistic that an effective vaccine is still possible.

“We cannot and will not lose hope that the world will have an effective HIV vaccine that is accessible by all who need it, anywhere,” International AIDS Society (IAS) Executive Director Birgit Poniatowski said in a statement in December, when the trial was stopped.

HIV is a still persistent problem in the United States, according to the Centers for Disease Control and Prevention that reports it has affected an estimated 1.2 million people.

With new people infected every day around the globe, Dr. Huang says she feels a sense of urgency to help. “I think about all the people around the globe and the large number of young girls being hurt and I know our big pool of talent can intervene to change what we see happening.” 

Dr. Huang says the clinical trial failures we’ve seen so far will help guide next steps in HIV research as much as successes typically do.
 

Advances in the Field

With significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, a new wave of clinical trials are on the way.

And with so many new approaches in the works, the HIV Vaccine Trials Network is retooling how it operates to navigate a burgeoning field and identify the most promising regimens.

A new Discovery Medicine Program will help the network assess new vaccine candidates. It will also aim to rule out others earlier on.

For COVID-19 and the flu, multimeric nanoparticles are an important alternative under investigation that could also be adapted for HIV.

Dr. Huang says she is particularly excited to watch the progress in cocktails of combination monoclonals. “I’ve been working in this field for 20 years now and there is a misconception that with pre-exposure prophylaxis, our job is done, but HIV is so far from away from being solved.”

But you just never know, Dr. Huang says. With new research, “we could bump on something at any point that changes everything.”

A version of this article appeared on Medscape.com.

Sandra Hong, MD, chair of allergy and immunology and director of the Food Allergy Center of Excellence at Cleveland Clinic, in Ohio, sees firsthand how situations that feel ordinary to most people strike fear in the hearts of her patients with food allergies. 

Not only do some experience reactions to milk when they eat a cheese pizza — they can’t be in the same room with someone enjoying a slice nearby. “That would be terrifying,” Dr. Hong said.

Omalizumab (Xolair), recently approved by the US Food and Drug Administration as monotherapy for the treatment of food allergies, may now bring peace of mind to these patients and their families by reducing their risk of dangerous allergic reactions to accidental exposure.

While the drug does not cure food allergies, a phase 3, placebo-controlled trial found that after 16 weeks of treatment, two thirds of participants were able to tolerate at least 600 mg of peanut protein — equal to about 2.5 peanuts — without experiencing moderate to severe reactions. 

An open-label extension trial also found the monoclonal antibody reduced the likelihood of serious reactions to eggs by 67%, milk by 66%, and cashews by 42%. The results of the study were published in The New England Journal of Medicine.

The treatment is approved for children as young as the age of 1 year and is the only treatment approved for multiple food allergies. It does not treat anaphylaxis or other emergency situations.

Patient Selection Key

While 8% of children and 10% of adults in the United States have a true food allergy, Brian Vickery, MD, chief of allergy and immunology and director of the Food Allergy Center at Children’s Healthcare of Atlanta, noted that a significantly higher proportion of the population restricts their diet based on perceived food intolerances.

“Most important for family doctors prior to prescribing the medication will be to be sure that the diagnosis is correct,” Kim said. “We know that allergy blood and skin testing is good but not perfect, and false positive results can occur,” said Edwin Kim, MD, chief of the Division of Pediatric Allergy and Immunology and director of the University of North Carolina Food Allergy Initiative at the University of North Carolina School of Medicine, Chapel Hill, who was a coauthor on the study in the New England Journal of Medicine. “ An allergist can conduct food challenges to confirm the diagnosis if results are unclear.”

Even for patients with confirmed IgE-mediated allergies, Dr. Hong said selecting patients who are good candidates for the therapy has “nuances.” 

Patients must be willing and able to commit to injections every 2-4 weeks. Dosing depends on body weight and the total IgE levels of each patient. Patients with IgE levels > 1850 UI/mL likely will be disqualified from treatment since the clinical trial did not enroll patients with total IgE above this level and the appropriate dose in those patients is unknown.

“My recommendation for family physicians who are counseling food-allergic patients interested in omalizumab treatment is to partner with an allergist-immunologist, if at all possible,” Dr. Vickery said. He added that patients should have a comprehensive workup before beginning treatment because starting omalizumab would reduce reactivity and alter the outcome a diagnostic oral food challenge.

Two populations Dr. Hong thinks might particularly benefit from the therapy are college students and preschoolers, who may be unable to completely avoid allergens because of poor impulse control and food sharing in group settings.

“The concerns we have about this age group are whether or not there might be other factors involved that may impede their ability to make good decisions.”

Less control of the environment in dorms or other group living situations also could increase the risk of accidental exposure to a food allergen.

For the right patients, the treatment regimen has significant advantages over oral immunotherapy treatment (OIT), including the fact that it’s not a daily medication and it has the potential to treat allergic asthma at the same time.

“The biggest pro for omalizumab is that it can treat all of your food allergies, whether you have one or many, and do it all in one medication,” Dr. Kim said. 

Managing Potential Harms

Omalizumab carries risks both primary care providers and patients must consider. First among them is that the drug carries a “black box” warning for an increased risk of anaphylaxis, Dr. Hong said. 

Although patients with multiple food allergies typically already have prescriptions for epinephrine, primary care physicians (PCPs) considering offering omalizumab must be comfortable treating severe systemic reactions and their offices capable of post-dose monitoring, Dr. Hong said. 

Anaphylaxis “can occur after the first dose or it can be delayed,” she said. “Typically, allergists will give these in our offices and we’ll actually have people wait for delayed amounts of time, for hours.”

The drug has been available since 2003 as a treatment for allergic asthma and urticaria. In addition to the warning for anaphylaxis, common reactions include joint pain and injection-site reactions. It also increases the risk for parasitic infection, and some studies show an increase in the risk for cancer.

Still, Dr. Kim said omalizumab’s safety profile is reassuring and noted it has advantages over OIT. “Since the patient is not exposing themselves to the food they are allergic to like in OIT, the safety is expected to be far better,” he said.

Lifelong Treatment 

Dr. Vickery, Dr. Hong, and Dr. Kim all cautioned that patients should understand that, while omalizumab offers protection against accidental exposure and can meaningfully improve quality of life, it won’t allow them to loosen their allergen-avoidant diets.

Further, maintaining protection requires receiving injections every 2-4 weeks for life. For those without insurance, or whose insurance does not cover the treatment, costs could reach thousands of dollars each month, Dr. Hong said.

Omalizumab “has been well covered by insurance for asthma and chronic hives, but we will have to see what it looks like for food allergy. The range of plans and out-of-pocket deductibles available to patients will also play a big role,” Dr. Kim said. 

Other novel approaches to food allergies are currently in clinical trials, and both Dr. Hong and Dr. Vickery are optimistic about potential options in the pipeline.

“We’re just on the brink of really exciting therapies coming forward in the future,” Dr. Hong said.

The study was supported by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, both part of the National Institutes of Health; the Claudia and Steve Stange Family Fund; Genentech; and Novartis. Dr. Hong, Dr. Kim, and Dr. Vickery reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Sandra Hong, MD, chair of allergy and immunology and director of the Food Allergy Center of Excellence at Cleveland Clinic, in Ohio, sees firsthand how situations that feel ordinary to most people strike fear in the hearts of her patients with food allergies. 

Not only do some experience reactions to milk when they eat a cheese pizza — they can’t be in the same room with someone enjoying a slice nearby. “That would be terrifying,” Dr. Hong said.

Omalizumab (Xolair), recently approved by the US Food and Drug Administration as monotherapy for the treatment of food allergies, may now bring peace of mind to these patients and their families by reducing their risk of dangerous allergic reactions to accidental exposure.

While the drug does not cure food allergies, a phase 3, placebo-controlled trial found that after 16 weeks of treatment, two thirds of participants were able to tolerate at least 600 mg of peanut protein — equal to about 2.5 peanuts — without experiencing moderate to severe reactions. 

An open-label extension trial also found the monoclonal antibody reduced the likelihood of serious reactions to eggs by 67%, milk by 66%, and cashews by 42%. The results of the study were published in The New England Journal of Medicine.

The treatment is approved for children as young as the age of 1 year and is the only treatment approved for multiple food allergies. It does not treat anaphylaxis or other emergency situations.

Patient Selection Key

While 8% of children and 10% of adults in the United States have a true food allergy, Brian Vickery, MD, chief of allergy and immunology and director of the Food Allergy Center at Children’s Healthcare of Atlanta, noted that a significantly higher proportion of the population restricts their diet based on perceived food intolerances.

“Most important for family doctors prior to prescribing the medication will be to be sure that the diagnosis is correct,” Kim said. “We know that allergy blood and skin testing is good but not perfect, and false positive results can occur,” said Edwin Kim, MD, chief of the Division of Pediatric Allergy and Immunology and director of the University of North Carolina Food Allergy Initiative at the University of North Carolina School of Medicine, Chapel Hill, who was a coauthor on the study in the New England Journal of Medicine. “ An allergist can conduct food challenges to confirm the diagnosis if results are unclear.”

Even for patients with confirmed IgE-mediated allergies, Dr. Hong said selecting patients who are good candidates for the therapy has “nuances.” 

Patients must be willing and able to commit to injections every 2-4 weeks. Dosing depends on body weight and the total IgE levels of each patient. Patients with IgE levels > 1850 UI/mL likely will be disqualified from treatment since the clinical trial did not enroll patients with total IgE above this level and the appropriate dose in those patients is unknown.

“My recommendation for family physicians who are counseling food-allergic patients interested in omalizumab treatment is to partner with an allergist-immunologist, if at all possible,” Dr. Vickery said. He added that patients should have a comprehensive workup before beginning treatment because starting omalizumab would reduce reactivity and alter the outcome a diagnostic oral food challenge.

Two populations Dr. Hong thinks might particularly benefit from the therapy are college students and preschoolers, who may be unable to completely avoid allergens because of poor impulse control and food sharing in group settings.

“The concerns we have about this age group are whether or not there might be other factors involved that may impede their ability to make good decisions.”

Less control of the environment in dorms or other group living situations also could increase the risk of accidental exposure to a food allergen.

For the right patients, the treatment regimen has significant advantages over oral immunotherapy treatment (OIT), including the fact that it’s not a daily medication and it has the potential to treat allergic asthma at the same time.

“The biggest pro for omalizumab is that it can treat all of your food allergies, whether you have one or many, and do it all in one medication,” Dr. Kim said. 

Managing Potential Harms

Omalizumab carries risks both primary care providers and patients must consider. First among them is that the drug carries a “black box” warning for an increased risk of anaphylaxis, Dr. Hong said. 

Although patients with multiple food allergies typically already have prescriptions for epinephrine, primary care physicians (PCPs) considering offering omalizumab must be comfortable treating severe systemic reactions and their offices capable of post-dose monitoring, Dr. Hong said. 

Anaphylaxis “can occur after the first dose or it can be delayed,” she said. “Typically, allergists will give these in our offices and we’ll actually have people wait for delayed amounts of time, for hours.”

The drug has been available since 2003 as a treatment for allergic asthma and urticaria. In addition to the warning for anaphylaxis, common reactions include joint pain and injection-site reactions. It also increases the risk for parasitic infection, and some studies show an increase in the risk for cancer.

Still, Dr. Kim said omalizumab’s safety profile is reassuring and noted it has advantages over OIT. “Since the patient is not exposing themselves to the food they are allergic to like in OIT, the safety is expected to be far better,” he said.

Lifelong Treatment 

Dr. Vickery, Dr. Hong, and Dr. Kim all cautioned that patients should understand that, while omalizumab offers protection against accidental exposure and can meaningfully improve quality of life, it won’t allow them to loosen their allergen-avoidant diets.

Further, maintaining protection requires receiving injections every 2-4 weeks for life. For those without insurance, or whose insurance does not cover the treatment, costs could reach thousands of dollars each month, Dr. Hong said.

Omalizumab “has been well covered by insurance for asthma and chronic hives, but we will have to see what it looks like for food allergy. The range of plans and out-of-pocket deductibles available to patients will also play a big role,” Dr. Kim said. 

Other novel approaches to food allergies are currently in clinical trials, and both Dr. Hong and Dr. Vickery are optimistic about potential options in the pipeline.

“We’re just on the brink of really exciting therapies coming forward in the future,” Dr. Hong said.

The study was supported by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, both part of the National Institutes of Health; the Claudia and Steve Stange Family Fund; Genentech; and Novartis. Dr. Hong, Dr. Kim, and Dr. Vickery reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Sandra Hong, MD, chair of allergy and immunology and director of the Food Allergy Center of Excellence at Cleveland Clinic, in Ohio, sees firsthand how situations that feel ordinary to most people strike fear in the hearts of her patients with food allergies. 

Not only do some experience reactions to milk when they eat a cheese pizza — they can’t be in the same room with someone enjoying a slice nearby. “That would be terrifying,” Dr. Hong said.

Omalizumab (Xolair), recently approved by the US Food and Drug Administration as monotherapy for the treatment of food allergies, may now bring peace of mind to these patients and their families by reducing their risk of dangerous allergic reactions to accidental exposure.

While the drug does not cure food allergies, a phase 3, placebo-controlled trial found that after 16 weeks of treatment, two thirds of participants were able to tolerate at least 600 mg of peanut protein — equal to about 2.5 peanuts — without experiencing moderate to severe reactions. 

An open-label extension trial also found the monoclonal antibody reduced the likelihood of serious reactions to eggs by 67%, milk by 66%, and cashews by 42%. The results of the study were published in The New England Journal of Medicine.

The treatment is approved for children as young as the age of 1 year and is the only treatment approved for multiple food allergies. It does not treat anaphylaxis or other emergency situations.

Patient Selection Key

While 8% of children and 10% of adults in the United States have a true food allergy, Brian Vickery, MD, chief of allergy and immunology and director of the Food Allergy Center at Children’s Healthcare of Atlanta, noted that a significantly higher proportion of the population restricts their diet based on perceived food intolerances.

“Most important for family doctors prior to prescribing the medication will be to be sure that the diagnosis is correct,” Kim said. “We know that allergy blood and skin testing is good but not perfect, and false positive results can occur,” said Edwin Kim, MD, chief of the Division of Pediatric Allergy and Immunology and director of the University of North Carolina Food Allergy Initiative at the University of North Carolina School of Medicine, Chapel Hill, who was a coauthor on the study in the New England Journal of Medicine. “ An allergist can conduct food challenges to confirm the diagnosis if results are unclear.”

Even for patients with confirmed IgE-mediated allergies, Dr. Hong said selecting patients who are good candidates for the therapy has “nuances.” 

Patients must be willing and able to commit to injections every 2-4 weeks. Dosing depends on body weight and the total IgE levels of each patient. Patients with IgE levels > 1850 UI/mL likely will be disqualified from treatment since the clinical trial did not enroll patients with total IgE above this level and the appropriate dose in those patients is unknown.

“My recommendation for family physicians who are counseling food-allergic patients interested in omalizumab treatment is to partner with an allergist-immunologist, if at all possible,” Dr. Vickery said. He added that patients should have a comprehensive workup before beginning treatment because starting omalizumab would reduce reactivity and alter the outcome a diagnostic oral food challenge.

Two populations Dr. Hong thinks might particularly benefit from the therapy are college students and preschoolers, who may be unable to completely avoid allergens because of poor impulse control and food sharing in group settings.

“The concerns we have about this age group are whether or not there might be other factors involved that may impede their ability to make good decisions.”

Less control of the environment in dorms or other group living situations also could increase the risk of accidental exposure to a food allergen.

For the right patients, the treatment regimen has significant advantages over oral immunotherapy treatment (OIT), including the fact that it’s not a daily medication and it has the potential to treat allergic asthma at the same time.

“The biggest pro for omalizumab is that it can treat all of your food allergies, whether you have one or many, and do it all in one medication,” Dr. Kim said. 

Managing Potential Harms

Omalizumab carries risks both primary care providers and patients must consider. First among them is that the drug carries a “black box” warning for an increased risk of anaphylaxis, Dr. Hong said. 

Although patients with multiple food allergies typically already have prescriptions for epinephrine, primary care physicians (PCPs) considering offering omalizumab must be comfortable treating severe systemic reactions and their offices capable of post-dose monitoring, Dr. Hong said. 

Anaphylaxis “can occur after the first dose or it can be delayed,” she said. “Typically, allergists will give these in our offices and we’ll actually have people wait for delayed amounts of time, for hours.”

The drug has been available since 2003 as a treatment for allergic asthma and urticaria. In addition to the warning for anaphylaxis, common reactions include joint pain and injection-site reactions. It also increases the risk for parasitic infection, and some studies show an increase in the risk for cancer.

Still, Dr. Kim said omalizumab’s safety profile is reassuring and noted it has advantages over OIT. “Since the patient is not exposing themselves to the food they are allergic to like in OIT, the safety is expected to be far better,” he said.

Lifelong Treatment 

Dr. Vickery, Dr. Hong, and Dr. Kim all cautioned that patients should understand that, while omalizumab offers protection against accidental exposure and can meaningfully improve quality of life, it won’t allow them to loosen their allergen-avoidant diets.

Further, maintaining protection requires receiving injections every 2-4 weeks for life. For those without insurance, or whose insurance does not cover the treatment, costs could reach thousands of dollars each month, Dr. Hong said.

Omalizumab “has been well covered by insurance for asthma and chronic hives, but we will have to see what it looks like for food allergy. The range of plans and out-of-pocket deductibles available to patients will also play a big role,” Dr. Kim said. 

Other novel approaches to food allergies are currently in clinical trials, and both Dr. Hong and Dr. Vickery are optimistic about potential options in the pipeline.

“We’re just on the brink of really exciting therapies coming forward in the future,” Dr. Hong said.

The study was supported by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, both part of the National Institutes of Health; the Claudia and Steve Stange Family Fund; Genentech; and Novartis. Dr. Hong, Dr. Kim, and Dr. Vickery reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

The smallpox vaccine effectively induces immunity against mpox virus infection (formerly simian smallpox) in patients with human immunodeficiency virus (HIV) infection, although patients with lymphocyte counts below 500 cells/mm³ require booster doses, according to data from a study published in the Journal of Medical Virology.

The data come from the prospective observational study conducted by researchers at the Infection Biology Laboratory of the Department of Medicine and Life Sciences at Pompeu Fabra University and the HIV Unit of the Hospital del Mar Medical Research Institute in Barcelona, Spain. The investigators analyzed T-cell responses induced by vaccination with JYNNEOS.

Despite the substantial decrease in the reporting frequency of mpox cases from the global peak in August 2022 (30,894 cases) to 804 monthly cases in the last six months of 2023, mpox continues to circulate, and there is no specific vaccine. The JYNNEOS vaccine, with protective cross-reactivity against orthopoxviruses, is approved by the US Food and Drug Administration and the European Medicines Agency for the prevention of smallpox and mpox in adults at high risk for infection.

During the 2022 outbreak in the United States and Europe, vaccine shortages led to the emergency use authorization of a lower intradermal dose. This strategy was aimed at increasing vaccine supply up to fivefold.

Further clinical trials are needed to evaluate responses to JYNNEOS vaccination and compare different administration routes in patients with HIV infection. Protecting this population against mpox is a priority because people with high viral loads or loCD4+ T-lymphocyte counts are especially susceptible to severe disease.
 

Vaccination Responses 

The study assessed the immune response to the JYNNEOS vaccine in patients with HIV who were receiving antiretroviral therapy as outpatients at the Infectious Diseases Unit of Hospital del Mar in Barcelona, Spain. Participants had viral loads controlled by antiretroviral therapy and CD4+ T-lymphocyte counts ≤ 500/mm³ (loCD4 group) or ≥ 500/mm³ (hiCD4 group) in blood. Vaccine responses were compared with those of vaccinated controls without the disease. The study included cases that received the standard subcutaneous vaccine (before August 2022) or the emergency dose-saving intradermal vaccine after its approval in August 2022.

The results demonstrated that the intradermal dose-saving vaccination route is preferable to the subcutaneous route and that patients in the loCD4 group may require at least one booster to generate an efficient response of specific T cells for mpox, wrote the authors.

“This study has two relevant points,” study author Robert Güerri-Fernandez, MD, PhD, head of infectious diseases at the Hospital del Mar Medical Research Institute, told this news organization. “In the subgroup of patients with HIV with effective treatment but without an immune response (ie, loCD4), the vaccine response is worse than in people who have recovered immunity or do not have HIV. Therefore, they need a booster dose.

“The second point is that the intradermal route with one-fifth of the standard subcutaneous dose has a better immune response than the standard subcutaneous route.” He added that it was a good strategy to save doses and be able to vaccinate many more people when vaccine shortages occurred.

“A general conclusion cannot be drawn,” he said. “It needs to be validated with many more subjects, of course, but in some way, it reinforced our confidence in the strategy of health authorities to promote intradermal vaccination. There we had evidence that the patients we were vaccinating intradermally were responding well.”

In Spain, although there is no shortage of vaccines today, they continue to be administered intradermally with a fractionated dose equivalent to one fifth of a standard dose, said Dr. Güerri-Fernandez.

However, in his opinion, observations regarding the two administration routes signal a need for further research. The main message should be that for patients with HIV infection who do not have an immune response, the vaccine response is incomplete, and they need booster doses as well as monitoring of the vaccine immune response, said Dr. Güerri-Fernandez.
 

More Studies Required

The research, which prospectively collected data and blood samples from patients with HIV who received the JYNNEOS vaccine, is small and included only 24 patients with HIV infection, with seven hospital workers who also received the vaccine and seven unvaccinated individuals as controls. “I am one of the control subjects of the study, and intradermal vaccination is not especially pleasant,” said Dr. Güerri-Fernandez. “It is a very innervated area, and the moment of introducing the liquid is uncomfortable. But it is perfectly bearable.”

Outpatient HIV-infected patients from the Infectious Diseases Unit of Hospital del Mar on antiretroviral therapy and with undetectable viral loads were grouped according to their CD4+ T-lymphocyte counts. Those with CD4+ T-lymphocyte counts ≤ 500/mm³ required at least one booster vaccine to exhibit efficient virus-specific T-lymphocyte responses. The magnitude of the T-cell response after this booster correlated directly with the CD4+ T-lymphocyte count of those vaccinated.

For Argentine infectious disease specialist Julián García, MD, clinical researcher at the Huésped Foundation in Buenos Aires, Argentina, who did not participate in the study, it is always productive to know that T-cell responses develop in patients with HIV infection, with CD4+ T-lymphocyte counts > and < 500/mm^3, through an intradermal administration route.

Dr. García emphasized that the most novel aspect is that the JYNNEOS vaccine induces a specific T-cell response in patients with HIV infection that increases with higher CD4+ T-lymphocyte levels. However, he noted that the number of patients was less than 10 in most study groups, and the control group had only intradermal administration, which limits the interpretation of the results. “It will be necessary to verify this in studies with larger groups with control groups from all routes and with a correlate of protection.”

Dr. García referred to this latter point as a significant source of uncertainty. “The study is fundamentally based on the cellular response, but nowadays, there is no immune correlate of real-life protection.” He concluded that the study builds knowledge, which is essential for a vaccine that began to be used for mpox and the effectiveness of which is based on estimates. 

Dr. Güerri-Fernandez and Dr. Garcia declared no relevant financial conflicts of interest. 

This story was translated from the Medscape Spanish edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The smallpox vaccine effectively induces immunity against mpox virus infection (formerly simian smallpox) in patients with human immunodeficiency virus (HIV) infection, although patients with lymphocyte counts below 500 cells/mm³ require booster doses, according to data from a study published in the Journal of Medical Virology.

The data come from the prospective observational study conducted by researchers at the Infection Biology Laboratory of the Department of Medicine and Life Sciences at Pompeu Fabra University and the HIV Unit of the Hospital del Mar Medical Research Institute in Barcelona, Spain. The investigators analyzed T-cell responses induced by vaccination with JYNNEOS.

Despite the substantial decrease in the reporting frequency of mpox cases from the global peak in August 2022 (30,894 cases) to 804 monthly cases in the last six months of 2023, mpox continues to circulate, and there is no specific vaccine. The JYNNEOS vaccine, with protective cross-reactivity against orthopoxviruses, is approved by the US Food and Drug Administration and the European Medicines Agency for the prevention of smallpox and mpox in adults at high risk for infection.

During the 2022 outbreak in the United States and Europe, vaccine shortages led to the emergency use authorization of a lower intradermal dose. This strategy was aimed at increasing vaccine supply up to fivefold.

Further clinical trials are needed to evaluate responses to JYNNEOS vaccination and compare different administration routes in patients with HIV infection. Protecting this population against mpox is a priority because people with high viral loads or loCD4+ T-lymphocyte counts are especially susceptible to severe disease.
 

Vaccination Responses 

The study assessed the immune response to the JYNNEOS vaccine in patients with HIV who were receiving antiretroviral therapy as outpatients at the Infectious Diseases Unit of Hospital del Mar in Barcelona, Spain. Participants had viral loads controlled by antiretroviral therapy and CD4+ T-lymphocyte counts ≤ 500/mm³ (loCD4 group) or ≥ 500/mm³ (hiCD4 group) in blood. Vaccine responses were compared with those of vaccinated controls without the disease. The study included cases that received the standard subcutaneous vaccine (before August 2022) or the emergency dose-saving intradermal vaccine after its approval in August 2022.

The results demonstrated that the intradermal dose-saving vaccination route is preferable to the subcutaneous route and that patients in the loCD4 group may require at least one booster to generate an efficient response of specific T cells for mpox, wrote the authors.

“This study has two relevant points,” study author Robert Güerri-Fernandez, MD, PhD, head of infectious diseases at the Hospital del Mar Medical Research Institute, told this news organization. “In the subgroup of patients with HIV with effective treatment but without an immune response (ie, loCD4), the vaccine response is worse than in people who have recovered immunity or do not have HIV. Therefore, they need a booster dose.

“The second point is that the intradermal route with one-fifth of the standard subcutaneous dose has a better immune response than the standard subcutaneous route.” He added that it was a good strategy to save doses and be able to vaccinate many more people when vaccine shortages occurred.

“A general conclusion cannot be drawn,” he said. “It needs to be validated with many more subjects, of course, but in some way, it reinforced our confidence in the strategy of health authorities to promote intradermal vaccination. There we had evidence that the patients we were vaccinating intradermally were responding well.”

In Spain, although there is no shortage of vaccines today, they continue to be administered intradermally with a fractionated dose equivalent to one fifth of a standard dose, said Dr. Güerri-Fernandez.

However, in his opinion, observations regarding the two administration routes signal a need for further research. The main message should be that for patients with HIV infection who do not have an immune response, the vaccine response is incomplete, and they need booster doses as well as monitoring of the vaccine immune response, said Dr. Güerri-Fernandez.
 

More Studies Required

The research, which prospectively collected data and blood samples from patients with HIV who received the JYNNEOS vaccine, is small and included only 24 patients with HIV infection, with seven hospital workers who also received the vaccine and seven unvaccinated individuals as controls. “I am one of the control subjects of the study, and intradermal vaccination is not especially pleasant,” said Dr. Güerri-Fernandez. “It is a very innervated area, and the moment of introducing the liquid is uncomfortable. But it is perfectly bearable.”

Outpatient HIV-infected patients from the Infectious Diseases Unit of Hospital del Mar on antiretroviral therapy and with undetectable viral loads were grouped according to their CD4+ T-lymphocyte counts. Those with CD4+ T-lymphocyte counts ≤ 500/mm³ required at least one booster vaccine to exhibit efficient virus-specific T-lymphocyte responses. The magnitude of the T-cell response after this booster correlated directly with the CD4+ T-lymphocyte count of those vaccinated.

For Argentine infectious disease specialist Julián García, MD, clinical researcher at the Huésped Foundation in Buenos Aires, Argentina, who did not participate in the study, it is always productive to know that T-cell responses develop in patients with HIV infection, with CD4+ T-lymphocyte counts > and < 500/mm^3, through an intradermal administration route.

Dr. García emphasized that the most novel aspect is that the JYNNEOS vaccine induces a specific T-cell response in patients with HIV infection that increases with higher CD4+ T-lymphocyte levels. However, he noted that the number of patients was less than 10 in most study groups, and the control group had only intradermal administration, which limits the interpretation of the results. “It will be necessary to verify this in studies with larger groups with control groups from all routes and with a correlate of protection.”

Dr. García referred to this latter point as a significant source of uncertainty. “The study is fundamentally based on the cellular response, but nowadays, there is no immune correlate of real-life protection.” He concluded that the study builds knowledge, which is essential for a vaccine that began to be used for mpox and the effectiveness of which is based on estimates. 

Dr. Güerri-Fernandez and Dr. Garcia declared no relevant financial conflicts of interest. 

This story was translated from the Medscape Spanish edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

The smallpox vaccine effectively induces immunity against mpox virus infection (formerly simian smallpox) in patients with human immunodeficiency virus (HIV) infection, although patients with lymphocyte counts below 500 cells/mm³ require booster doses, according to data from a study published in the Journal of Medical Virology.

The data come from the prospective observational study conducted by researchers at the Infection Biology Laboratory of the Department of Medicine and Life Sciences at Pompeu Fabra University and the HIV Unit of the Hospital del Mar Medical Research Institute in Barcelona, Spain. The investigators analyzed T-cell responses induced by vaccination with JYNNEOS.

Despite the substantial decrease in the reporting frequency of mpox cases from the global peak in August 2022 (30,894 cases) to 804 monthly cases in the last six months of 2023, mpox continues to circulate, and there is no specific vaccine. The JYNNEOS vaccine, with protective cross-reactivity against orthopoxviruses, is approved by the US Food and Drug Administration and the European Medicines Agency for the prevention of smallpox and mpox in adults at high risk for infection.

During the 2022 outbreak in the United States and Europe, vaccine shortages led to the emergency use authorization of a lower intradermal dose. This strategy was aimed at increasing vaccine supply up to fivefold.

Further clinical trials are needed to evaluate responses to JYNNEOS vaccination and compare different administration routes in patients with HIV infection. Protecting this population against mpox is a priority because people with high viral loads or loCD4+ T-lymphocyte counts are especially susceptible to severe disease.
 

Vaccination Responses 

The study assessed the immune response to the JYNNEOS vaccine in patients with HIV who were receiving antiretroviral therapy as outpatients at the Infectious Diseases Unit of Hospital del Mar in Barcelona, Spain. Participants had viral loads controlled by antiretroviral therapy and CD4+ T-lymphocyte counts ≤ 500/mm³ (loCD4 group) or ≥ 500/mm³ (hiCD4 group) in blood. Vaccine responses were compared with those of vaccinated controls without the disease. The study included cases that received the standard subcutaneous vaccine (before August 2022) or the emergency dose-saving intradermal vaccine after its approval in August 2022.

The results demonstrated that the intradermal dose-saving vaccination route is preferable to the subcutaneous route and that patients in the loCD4 group may require at least one booster to generate an efficient response of specific T cells for mpox, wrote the authors.

“This study has two relevant points,” study author Robert Güerri-Fernandez, MD, PhD, head of infectious diseases at the Hospital del Mar Medical Research Institute, told this news organization. “In the subgroup of patients with HIV with effective treatment but without an immune response (ie, loCD4), the vaccine response is worse than in people who have recovered immunity or do not have HIV. Therefore, they need a booster dose.

“The second point is that the intradermal route with one-fifth of the standard subcutaneous dose has a better immune response than the standard subcutaneous route.” He added that it was a good strategy to save doses and be able to vaccinate many more people when vaccine shortages occurred.

“A general conclusion cannot be drawn,” he said. “It needs to be validated with many more subjects, of course, but in some way, it reinforced our confidence in the strategy of health authorities to promote intradermal vaccination. There we had evidence that the patients we were vaccinating intradermally were responding well.”

In Spain, although there is no shortage of vaccines today, they continue to be administered intradermally with a fractionated dose equivalent to one fifth of a standard dose, said Dr. Güerri-Fernandez.

However, in his opinion, observations regarding the two administration routes signal a need for further research. The main message should be that for patients with HIV infection who do not have an immune response, the vaccine response is incomplete, and they need booster doses as well as monitoring of the vaccine immune response, said Dr. Güerri-Fernandez.
 

More Studies Required

The research, which prospectively collected data and blood samples from patients with HIV who received the JYNNEOS vaccine, is small and included only 24 patients with HIV infection, with seven hospital workers who also received the vaccine and seven unvaccinated individuals as controls. “I am one of the control subjects of the study, and intradermal vaccination is not especially pleasant,” said Dr. Güerri-Fernandez. “It is a very innervated area, and the moment of introducing the liquid is uncomfortable. But it is perfectly bearable.”

Outpatient HIV-infected patients from the Infectious Diseases Unit of Hospital del Mar on antiretroviral therapy and with undetectable viral loads were grouped according to their CD4+ T-lymphocyte counts. Those with CD4+ T-lymphocyte counts ≤ 500/mm³ required at least one booster vaccine to exhibit efficient virus-specific T-lymphocyte responses. The magnitude of the T-cell response after this booster correlated directly with the CD4+ T-lymphocyte count of those vaccinated.

For Argentine infectious disease specialist Julián García, MD, clinical researcher at the Huésped Foundation in Buenos Aires, Argentina, who did not participate in the study, it is always productive to know that T-cell responses develop in patients with HIV infection, with CD4+ T-lymphocyte counts > and < 500/mm^3, through an intradermal administration route.

Dr. García emphasized that the most novel aspect is that the JYNNEOS vaccine induces a specific T-cell response in patients with HIV infection that increases with higher CD4+ T-lymphocyte levels. However, he noted that the number of patients was less than 10 in most study groups, and the control group had only intradermal administration, which limits the interpretation of the results. “It will be necessary to verify this in studies with larger groups with control groups from all routes and with a correlate of protection.”

Dr. García referred to this latter point as a significant source of uncertainty. “The study is fundamentally based on the cellular response, but nowadays, there is no immune correlate of real-life protection.” He concluded that the study builds knowledge, which is essential for a vaccine that began to be used for mpox and the effectiveness of which is based on estimates. 

Dr. Güerri-Fernandez and Dr. Garcia declared no relevant financial conflicts of interest. 

This story was translated from the Medscape Spanish edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

Postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a distinct, centrally mediated condition, with evidence of autonomic, immune, and metabolic dysfunction, new "deep phenotyping" data suggested.

The study was initiated in 2016 at the US National Institutes of Health. Its aim was to better elucidate the underlying pathophysiology of ME/CFS, a multisystem disorder characterized by persistent and disabling fatigue, post-exertional malaise, cognitive complaints, and other physical symptoms. A total of 17 carefully selected individuals with PI-ME/CFS onset within the prior 5 years were compared with 21 healthy volunteers on a more extensive set of biologic measurements than has been examined in any prior study of the condition.

Overall, the findings suggested that ME/CFS is “a distinct entity characterized by somatic and cognitive complaints that are centrally mediated,” with fatigue that is “defined by effort preferences and central autonomic dysfunction,” Brian T. Walitt, MD, of the National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, Maryland, and colleagues wrote in the paper, published on February 21 in Nature Communications.

In addition, “there are distinct sex signatures of immune and metabolic dysregulation which suggest persistent antigenic stimulation.” Physical deconditioning over time, while not the source of the condition, “is an important consequence,” the authors added.

Asked to comment, Hector Bonilla, MD, director of the ME/CFS Clinic and codirector of the Stanford Post-Acute COVID-19 Syndrome Clinic, Atherton, California, pointed out that the sample was small and the study was cross-sectional and therefore likely missed dynamic changes in the patients.

Nonetheless, Dr. Bonilla told this news organization, “they have shown clear objective changes in patients with ME/CFS not seen in the controls. These are present in the microbiome, in the immune system, and in metabolites, especially in spinal fluid, that lead to a neuroinflammatory condition. And these are linked with autonomic dysfunction that can explain many of the symptoms that patients experience ... The symptoms are not manufactured by them.”

Thus far, the only treatments for ME/CFS are symptomatic. Understanding the pathophysiology is essential to identifying disease-modifying therapy, study lead author Avindra Nath, MD, Senior Investigator and Clinical Director of Intramural Research at NINDS, told this news organization.

“The disease is real. But our medical profession is limited in what they can do to diagnose or impact them ... The first thing we need to do is try to understand the pathophysiology. So that’s why the study was put together,” Dr. Nath said.

Postinfectious syndromes including ME/CFS have been given many names, including post-Lyme disease, Gulf War illness, and more recently, long COVID. With ME/CFS, the Epstein-Barr virus has historically been one of the most commonly associated triggers, although several other viral, bacterial, and environmental toxins have been implicated.

“There are a whole host of these things that have very similar symptoms or overlapping symptoms ... It’s quite possible that the underlying pathophysiology overlaps between all these syndromes,” Dr. Nath noted.

Another ME/CFS expert not involved in the study, researcher Michael VanElzakker, PhD, of the Neurotherapeutics Division at Harvard Medical School and Massachusetts General Hospital, Boston, said that the possibility of antigen persistence of the infectious pathogen arising from the immune system profiling conducted in the study is noteworthy and merits further study.

“To me, the obvious next step would be techniques like tissue-based assays and T-cell sequencing to try and understand what exactly those antigens are and what their source might be. Importantly, it is probably not the same antigen or pathogen source in all patients, but that’s a question that needs an answer,” Dr. VanElzakker said.

Of note, the 17 study participants had been adjudicated by an expert panel from an initial 484 inquiries and 217 who underwent detailed case reviews. They had to meet at least one of three published ME/CFS criteria and to have moderate to severe clinical symptom severity as determined by several fatigue scores. None met the criteria for psychiatric diagnoses.

Yet, even in the cases that met study criteria, underlying causes emerged in 20% of the participants over time, suggesting diagnostic misattribution. “This misclassification bias has important ramifications on the interpretation of the existing ME/CFS research literature,” the authors wrote.

Dr. VanElzakker noted, “The fact that this research study was probably the most detailed workup many of these patients had ever gotten is a serious indictment of our current profit-based healthcare system’s prioritization of 15-minute doctor’s appointments. It is almost certain that other patients would also benefit from an intensive detailed workup.”
 

Multiple Abnormalities Identified

There were no differences between the PI-ME/CFS and control groups in ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition, suggesting the absence of a resting low-energy state, the authors said.

In 40-minute head-up tilt-table testing, there were no differences between the ME/CFS and control groups in frequency or orthostatic hypotension or extensive orthostatic tachycardia. However, a 24-hour ambulatory electrocardiogram showed that the patients with PI-ME/CFS had diminished heart rate variability. They also showed increased heart rate throughout the day, suggesting increased sympathetic activity, and a diminished drop in nighttime heart rate, suggesting decreased parasympathetic activity.

“Considered together, these data suggest that there is an alteration in autonomic tone, implying central nervous system regulatory change,” Dr. Walitt and colleagues wrote.

On the “Effort-Expenditure for Rewards Task,” the participants with PI-ME/CFS showed significant differences in “effort preference,” or a tendency to avoid the harder tasks, as well as a slowing of button-pushing over time, compared with the controls, even with easier tasks. This pattern suggests that those with PI-ME/CFS were “pacing to limit exertion and associated feelings of discomfort,” the authors wrote.

Dr. Nath describes this behavior as akin to “if you develop a flu, you feel that you just want to lay down in bed and not hurt yourself. It’s not that you’re not capable of doing [the task], but your body tells you don’t do it. Your body just wants to fight the infection ... these people just never bounce back.”

Compared with the controls, the participants with PI-ME/CFS failed to maintain a moderate grip force even though there was no difference in maximum grip strength or arm muscle mass. This performance difference correlated with decreased activity of the right temporal-parietal junction, a novel observation suggesting that the fatigue in the PI-ME/CFS group “is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored,” Dr. Walitt and colleagues wrote.

On cardiopulmonary testing, peak power, peak respiratory rate, peak heart rate, and peak VO₂ were all lower in the PI-ME/CFS group, correlating to a difference of approximately 3.3 metabolic equivalent of task units. The differential cardiorespiratory performance relates to “autonomic function, hypothalamic-pituitary-adrenal axis hyporesponsiveness, and muscular deconditioning from disuse that clinically impacts activities of daily life,” they said.

In the participants with PI-ME/CFS, catechol levels in cerebrospinal fluid correlated with grip strength and effort preference, and several metabolites of the dopamine pathway correlated with several cognitive symptoms.

“This suggests that central nervous system catechol pathways are dysregulated in PI-ME/CFS and may play a role in effort preference and cognitive complaints,” as well as decreased central catecholamine biosynthesis. Similar findings have been seen in patients with long COVID, the authors noted.

There were increased naive B cells and decreased switched memory B cells in blood of participants with PI-ME/CFS. Contrary to prior studies, there was no consistent pattern of autoimmunity across all participants with PI-ME/CFS, and no previously undescribed antibodies were identified.

However, programmed cell death protein 1, a marker of T-cell exhaustion and activation, was elevated in the cerebrospinal fluid of the patients with PI-ME/CFS.

Several sex-based differences were noted, including in immune cell expression in cerebrospinal fluid, peripheral blood mononuclear cell gene expression, and muscle gene expression. Males and females also differed in the cerebrospinal metabolomics that distinguished the participants with PI-ME/CFS from controls.
 

What Do These Findings Suggest About Treatment?

The data point to several treatment implications. For one, the finding of possible immune exhaustion suggests that immune checkpoint inhibitors may be therapeutic by promoting clearance of foreign antigens. Immune dysfunction leads to neurochemical alterations that affect neuronal circuits, which may be another point of intervention, the authors suggested.

On the other hand, “attempting to target downstream mechanisms with exercise, cognitive behavioral therapy, or autonomic directed therapies may have limited impact on symptom burden, as it would not address the root cause of PI-ME/CFS,” they noted.

Combination therapy targeting multiple pathways along with a personalized medicine approach should be considered, they said.

“I think the most important thing is not to discount these patients,” Dr. Nath told this news organization. “They have a real disease, and we need to be empathetic towards them. We also need to make sure that they don’t have something underlying that is treatable, and then treat them symptomatically the best that you can. If not, then refer them to ME/CFS studies or clinics where people specialize in these conditions and work with them.”

The study authors and Dr. VanElzakker reported no relevant financial relationships. Dr. Bonilla consults for United Health and Resverlogix.
 

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I want to briefly discuss a critically important topic that cannot be overly emphasized. It is the relevance, the importance, the benefits, and the outcome of HPV vaccination.

The paper I’m referring to was published in Pediatrics in October 2023. It’s titled, “Ten-Year Follow-up of 9-Valent Human Papillomavirus Vaccine: Immunogenicity, Effectiveness, and Safety.”

Let me emphasize that we’re talking about a 10-year follow-up. In this particular paper and analysis, 301 boys — I emphasize boys — were included and 971 girls at 40 different sites in 13 countries, who received the 9-valent vaccine, which includes HPV 16, 18, and seven other types.

These investigators demonstrated that the seropositivity rate 10 years after vaccination remained high for all nine types they looked at. Most importantly, there was not a single case. Not one. Let me repeat this: There was not a single case of high-grade intraepithelial neoplasia, or worse, or condyloma in either males or females. There was not a single case in over 1000 individuals with a follow-up of more than 10 years.

It is difficult to overstate the magnitude of the benefit associated with HPV vaccination for our children and young adults on their risk of developing highly relevant, life-changing, potentially deadly cancers.

For those of you who are interested in this topic — which should include almost all of you, if not all of you — I encourage you to read this very important follow-up paper, again, demonstrating the simple, overwhelming magnitude of the benefit of HPV vaccination. I thank you for your attention.
 

Dr. Markman is a professor in the department of medical oncology and therapeutics research, City of Hope, Duarte, California, and president of medicine and science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed ties with GlaxoSmithKline; AstraZeneca.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I want to briefly discuss a critically important topic that cannot be overly emphasized. It is the relevance, the importance, the benefits, and the outcome of HPV vaccination.

The paper I’m referring to was published in Pediatrics in October 2023. It’s titled, “Ten-Year Follow-up of 9-Valent Human Papillomavirus Vaccine: Immunogenicity, Effectiveness, and Safety.”

Let me emphasize that we’re talking about a 10-year follow-up. In this particular paper and analysis, 301 boys — I emphasize boys — were included and 971 girls at 40 different sites in 13 countries, who received the 9-valent vaccine, which includes HPV 16, 18, and seven other types.

These investigators demonstrated that the seropositivity rate 10 years after vaccination remained high for all nine types they looked at. Most importantly, there was not a single case. Not one. Let me repeat this: There was not a single case of high-grade intraepithelial neoplasia, or worse, or condyloma in either males or females. There was not a single case in over 1000 individuals with a follow-up of more than 10 years.

It is difficult to overstate the magnitude of the benefit associated with HPV vaccination for our children and young adults on their risk of developing highly relevant, life-changing, potentially deadly cancers.

For those of you who are interested in this topic — which should include almost all of you, if not all of you — I encourage you to read this very important follow-up paper, again, demonstrating the simple, overwhelming magnitude of the benefit of HPV vaccination. I thank you for your attention.
 

Dr. Markman is a professor in the department of medical oncology and therapeutics research, City of Hope, Duarte, California, and president of medicine and science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed ties with GlaxoSmithKline; AstraZeneca.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

I want to briefly discuss a critically important topic that cannot be overly emphasized. It is the relevance, the importance, the benefits, and the outcome of HPV vaccination.

The paper I’m referring to was published in Pediatrics in October 2023. It’s titled, “Ten-Year Follow-up of 9-Valent Human Papillomavirus Vaccine: Immunogenicity, Effectiveness, and Safety.”

Let me emphasize that we’re talking about a 10-year follow-up. In this particular paper and analysis, 301 boys — I emphasize boys — were included and 971 girls at 40 different sites in 13 countries, who received the 9-valent vaccine, which includes HPV 16, 18, and seven other types.

These investigators demonstrated that the seropositivity rate 10 years after vaccination remained high for all nine types they looked at. Most importantly, there was not a single case. Not one. Let me repeat this: There was not a single case of high-grade intraepithelial neoplasia, or worse, or condyloma in either males or females. There was not a single case in over 1000 individuals with a follow-up of more than 10 years.

It is difficult to overstate the magnitude of the benefit associated with HPV vaccination for our children and young adults on their risk of developing highly relevant, life-changing, potentially deadly cancers.

For those of you who are interested in this topic — which should include almost all of you, if not all of you — I encourage you to read this very important follow-up paper, again, demonstrating the simple, overwhelming magnitude of the benefit of HPV vaccination. I thank you for your attention.
 

Dr. Markman is a professor in the department of medical oncology and therapeutics research, City of Hope, Duarte, California, and president of medicine and science, City of Hope Atlanta, Chicago, and Phoenix. He disclosed ties with GlaxoSmithKline; AstraZeneca.

A version of this article appeared on Medscape.com.