Virus World

One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as “long COVID”) which has emerged as a consequence of the SARS-CoV-2 epidemic. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. In this study, our goal was to assess the plasma metabolome in a total of 100 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC–MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin were measured in long COVID patients by immunoenzymatic assay.

The comparison of paired COVID-19/long COVID-19 samples revealed 53 metabolites that were statistically different. Compared to controls, 27 metabolites remained dysregulated even after two years. Post-COVID-19 patients displayed a heterogeneous metabolic profile. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients. Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.

Published in Scientific Reports (August 1, 2023):

https://doi.org/10.1038/s41598-023-39049-x 

The post-viral fatigue syndromes long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have multiple, potentially overlapping, pathological processes. These include persisting reservoirs of virus, e.g., SARS-CoV-2 in long COVID patient’s tissues, immune dysregulation with or without reactivation of underlying pathogens, such as Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV6), as we recently described in ME/CFS, and possibly yet unidentified viruses. In the present study we tested saliva samples from two cohorts for IgG against human adenovirus (HAdV): patients with ME/CFS (n = 84) and healthy controls (n = 94), with either mild/asymptomatic SARS-CoV-2 infection or no infection.

A significantly elevated anti-HAdV IgG response after SARS-CoV-2 infection was detected exclusively in the patient cohort. Longitudinal/time analysis, before and after COVID-19, in the very same individuals confirmed HAdV IgG elevation after. In plasma there was no HAdV IgG elevation. We conclude that COVID-19 triggered reactivation of dormant HAdV in the oral mucosa of chronic fatigue patients indicating an exhausted dysfunctional antiviral immune response in ME/CFS, allowing reactivation of adenovirus upon stress encounter such as COVID-19. These novel findings should be considered in clinical practice for identification of patients that may benefit from therapy that targets HAdV as well.

Published in Frontiers in Medicine (June 29, 2023):

https://doi.org/10.3389/fmed.2023.1208181 

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been associated mainly with a range of neurological symptoms, including brain fog and brain tissue loss, raising concerns about the virus's acute and potential chronic impact on the central nervous system. In this study, we utilized mouse models and human post-mortem tissues to investigate the presence and distribution of the SARS-CoV-2 spike protein in the skull-meninges-brain axis. Our results revealed the accumulation of the spike protein in the skull marrow, brain meninges, and brain parenchyma. The injection of the spike protein alone caused cell death in the brain, highlighting a direct effect on brain tissue. Furthermore, we observed the presence of spike protein in the skull of deceased long after their COVID-19 infection, suggesting that the spike's persistence may contribute to long-term neurological symptoms. The spike protein was associated with neutrophil-related pathways and dysregulation of the proteins involved in the PI3K-AKT as well as complement and coagulation pathway. Overall, our findings suggest that SARS-CoV-2 spike protein trafficking from CNS borders into the brain parenchyma and identified differentially regulated pathways may present insights into mechanisms underlying immediate and long-term consequences of SARS-CoV-2 and present diagnostic and therapeutic opportunities.

Preprint in bioRxiv (April 5, 2023):

https://doi.org/10.1101/2023.04.04.535604 

Significance

Abstract

A comprehensive evaluation of the risks and 1-year burdens of gastrointestinal disorders in the post-acute phase of COVID-19 is needed but is not yet available. Here we use the US Department of Veterans Affairs national health care databases to build a cohort of 154,068 people with COVID-19, 5,638,795 contemporary controls, and 5,859,621 historical controls to estimate the risks and 1-year burdens of a set of pre-specified incident gastrointestinal outcomes. We show that beyond the first 30 days of infection, people with COVID-19 exhibited increased risks and 1-year burdens of incident gastrointestinal disorders spanning several disease categories including motility disorders, acid related disorders (dyspepsia, gastroesophageal reflux disease, peptic ulcer disease), functional intestinal disorders, acute pancreatitis, hepatic and biliary disease.

The risks were evident in people who were not hospitalized during the acute phase of COVID-19 and increased in a graded fashion across the severity spectrum of the acute phase of COVID-19 (non-hospitalized, hospitalized, and admitted to intensive care). The risks were consistent in comparisons including the COVID-19 vs the contemporary control group and COVID-19 vs the historical control group as the referent category. Altogether, our results show that people with SARS-CoV-2 infection are at increased risk of gastrointestinal disorders in the post-acute phase of COVID-19. Post-covid care should involve attention to gastrointestinal health and disease. SARS-CoV-2 infection can lead to varied post-acute symptoms in the lungs and other organs, including the gastrointestinal system. Here the authors estimate the risks and 1-year burdens of a set of pre-specified incident gastrointestinal outcomes following SARS-CoV-2 infection in an electronic health care record-based cohort study.

Published in Nature Comm. (March 7, 2023):

https://www.nature.com/articles/s41467-023-36223-7 

Could taking Paxlovid reduce the risk of getting long COVID? Preliminary data suggests it might, but experts say there’s much more to learn. Long COVID, a wide-ranging set of sometimes debilitating symptomsfollowing a COVID infection, is a pressing and worrisome challenge for both patients and medical researchers, who are racing to figure out how to both prevent and treat the disease. Some evidence has emerged that Paxlovid, an oral antiviral medication used to treat COVID-19, can help reduce the risk of ending up with long COVID, experts said — and it’s one more reason to seek the treatment. Dr. Bob Wachter, UCSF’s chair of medicine, said in an email that the evidence, which comes from a study out of the Department of Veterans Affairs, isn’t huge, but shows Paxlovid can make “a meaningful difference” in warding off long COVID. It’s one of the reasons he’d take Paxlovid if he had COVID, he said. The November 2022 study of 56,000 people with COVID found that the more than 9,000 who took Paxlovid in the first five days of their infection had a 25% lower risk of long COVID symptoms, including heart disease, blood disorders, fatigue, liver disease, kidney disease, muscle pain, neurocognitive impairment and shortness of breath. In an interview with Wachter live streamed Thursday for the UCSF medical school’s grand rounds series, Dr. Eric Topol, director of the Scripps Research Translational Institute and a leading voice on COVID, agreed with Wachter, saying even the chance that Paxlovid helps prevent long COVID or reduce its severity is one of the main reasons to take the drug early.

SARS-CoV-2, responsible for the coronavirus disease (COVID-19) pandemic, may impact other systems apart from the respiratory system, including the nervous system. In this systematic review, we aimed to establish the prevalence and determinants of neuropathic pain amongst COVID-19-infected individuals. Methodology: A literature search in the PubMed database was performed and 11 papers were eligible for inclusion in this systematic review and meta-analysis. Results: The pooled prevalence of COVID-19-related neuropathic pain was 6.7% (95% CI: 4.7–9.5%) for hospitalised patients during the acute phase and 34.3% (95% CI: 14.3–62%) for long COVID patients. The identified risk factors for COVID-19-related neuropathic pain development included depression, COVID-19 severity and azithromycin use. Conclusions: Neuropathic pain is a very common symptom in long COVID, indicating the urgency for further research in this direction.

Published in J. Clin. Med. (Feb. 20, 2023):

https://doi.org/10.3390/jcm12041672

Regular exercise, good quality sleep, and maintaining a healthy diet may be key to preventing long-term complications following COVID-19 infection. Researchers found women who followed a healthy lifestyle had half of the risk of developing long-COVID compared to those with unhealthy lifestyles.

Women who followed most aspects of a healthy lifestyle, including healthy body weight, not smoking, regular exercise, adequate sleep, high quality diet, and moderate alcohol consumption, had about half the risk of long COVID compared with women without any healthy lifestyle factors, according to a study led by Harvard T.H. Chan School of Public Health.

Source: Harvard

“With ongoing waves of COVID-19, long COVID has created a serious public health burden. Our findings raise the possibility that adopting more healthy behaviors may reduce the risk of developing long COVID,” said Andrea Roberts, senior research scientist in the Department of Environmental Health and senior author of the study. The study appears online February 6, 2023, in JAMA Internal Medicine. It’s estimated that 8-23 million Americans suffer from long COVID, which is defined as having COVID-19 symptoms four weeks or more after initial SARS-CoV-2 infection. Symptoms can include fatigue, fever, and a variety of respiratory, heart, neurological, and digestive symptoms. The researchers analyzed data from more than 32,000 female nurses in the Nurses’ Health Study II, who reported on lifestyle in 2015 and 2017 and reported history of SARS-CoV-2 infection from April 2020 to November 2021. During that time, more than 1,900 participants contracted COVID-19. Among these, 44% developed long COVID. Compared to women without any healthy lifestyle factors, those with five or six had 49% lower risk of long COVID. Among the six lifestyle factors, maintaining a healthy body weight and getting adequate sleep (seven to nine hours daily) were the ones most strongly associated with lower risk of long COVID.

The results also showed that, even among women who developed long COVID, those with a healthier pre-infection lifestyle had 30% lower risk of having symptoms that interfered with their daily life. The authors noted that one possible explanation for the associations they observed is that, based on prior research, an unhealthy lifestyle is associated with increased risk of chronic inflammation and immune dysregulation, which have been linked with increased risk of long COVID. “In the past decades, scientists have accumulated evidence that healthy lifestyle is good for overall health. However, in the U.S. for example, 70% of the population do not have a healthy body weight and 30% do not sleep enough. “Findings from this study suggest that simple lifestyle changes, such as having adequate sleep, may be beneficial for the prevention of long COVID,” said lead author Siwen Wang, research fellow in the Department of Nutrition. Other Harvard Chan School authors included Yanping Li, Yiyang Yue, Changzhen Yuan, Jorge Chavarro, and Shilpa Bhupathiraju.

Funding: Support for the study came from NIH NICHD grant 3R01HD094725-02S1. Other support includes grants U01HL145386, R24ES028521, U01 CA176726, R01 CA67262, and R01 HD057368 from the NIH, the Dean’s Fund for Scientific Advancement Acceleration Award from Harvard Chan School, and Massachusetts Consortium on Pathogen Readiness Evergrande COVID-19 Response Fund Award.

Research published in JAMA Internal Medicine (Feb. 6, 2023):

https://doi.org/10.1001/jamainternmed.2022.6555 

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations.

Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process. Long COVID is an often debilitating illness of severe symptoms that can develop during or following COVID-19. In this Review, Davis, McCorkell, Vogel and Topol explore our knowledge of long COVID and highlight key findings, including potential mechanisms, the overlap with other conditions and potential treatments. They also discuss challenges and recommendations for long COVID research and care.

Published in Nat Rev Microbiol (Jan. 2023):

https://doi.org/10.1038/s41579-022-00846-2

“Long COVID” in some may not be an entirely new entity, researchers say.  COVID can cause reservoirs of some viruses you’ve previously battled to reactivate, potentially leading to symptoms of chronic fatigue syndrome—a condition that resembles long COVID, a recent study found. You had COVID a few months ago and recovered—but things still aren’t quite right. When you stand up, you feel dizzy, and your heart races. Even routine tasks leave you feeling spent. And what was once a good night’s sleep no longer feels refreshing. Long COVID, right? It may not be so simple. A mild or even an asymptomatic case of COVID can cause reservoirs of some viruses you’ve previously battled to reactivate, potentially leading to symptoms of chronic fatigue syndrome—a condition that resembles long COVID, according to a recent study published in the journal Frontiers in Immunology. Researchers found herpes viruses like Epstein-Barr, one of the drivers behind mono, circulating in unvaccinated patients who had experienced COVID. In patients with chronic fatigue syndrome, antibody responses were stronger, signaling an immune system struggling to fight off the lingering viruses.

University of Alberta researchers have identified an amino acid that may play a key role in predicting poor clinical outcomes and the treatment of long COVID.  In research published today in Cell Reports Medicine, the team says it has developed a predictive test to determine which patients with COVID-19 will go on to develop longer-term symptoms and proposes a clinical trial of an already-approved supplement as a potential treatment. In the study, the team followed 117 Alberta patients who were admitted to hospital with acute COVID-19, taking blood samples upon admission and at six months, and examining their clinical records for 18 months. Fifty-five of the patients went on to develop severe post-COVID condition, or long COVID. Researchers analyzed the patients' blood for changes in proteins and metabolites, as well as signs of inflammation. They then reviewed results using machine learning and developed a predictive model composed of 20 molecules. They found their model predicted adverse clinical outcomes following discharge from acute infection with 83 per cent accuracy. The most striking difference the researchers found among patients was in their plasma levels of the amino acid taurine.

"Patients with lower levels of taurine had a lot more symptoms, more of them were hospitalized and there was an increased risk for mortality," says Oudit. "Patients that had high levels of taurine and maintained high levels of taurine in their blood had much fewer ongoing symptoms and did better." Taurine is an amino acid found in meat and fish and also produced by the human liver. It helps regulate several physiological functions including the immune system. Further study of the impact of taurine supplementation in humans is needed, says Oudit, whose team is now moving to initiate a Phase 3 clinical trial in patients with COVID-19 to test if they can minimize long COVID down the road.

Oudit is hopeful taurine will prove to have multisystem effects that would be of benefit to people experiencing a range of long COVID symptoms. In the meantime, he advises patience. "Patients should not go out and start consuming taurine in high levels to help with long COVID," he says. "Taurine supplements are relatively safe, but we need to get that evidence from a clinical trial."

Reserch cited published in Cell Reports Medicine (October 6, 2023):

https://doi.org/10.1016/j.xcrm.2023.101254

Close to one-fifth of kids with COVID-19 may still have lingering symptoms months after their initial infection, new research finds.  The review, of 31 international studies, found that over 16% of children and teenagers with COVID had problems such as sore throat, persistent fevers, fatigue and muscle weakness at least three months later. Experts said the findings add to a still-evolving picture of how COVID affects kids in the longer term. What is clear, they said, is that children can develop long COVID, and it is far from a rare occurrence. "This is not a trivial infection," said senior researcher Zulfiqar Bhutta, co-director of the Centre for Global Child Health at the Hospital for Sick Children in Toronto. "We need to take it seriously." He and his colleagues report the findings in Pediatrics. More than three years after the start of the pandemic, long COVID remains something of a mystery—and its effects on kids are no exception.

But studies are ongoing, said Dr. Melissa Stockwell, division chief of child and adolescent health at Columbia University Vagelos College of Physicians and Surgeons in New York City. Stockwell and colleagues at Columbia are part of a large national study called RECOVER, funded by the U.S. National Institutes of Health, which is aimed at better understanding the long-term effects of COVID in adults and children. Stockwell said that while it's hard to say exactly what percentage of kids develop long COVID, the evidence suggests it's between 10% and 20%. So the new findings align with that, she said. "It's really worrisome, because that's a very large number of kids," Stockwell said. Yet, she noted, "I don't think most people even know that kids get long COVID." Researchers are still trying to understand the underlying biology of long COVID—whether symptoms are driven by persistent virus in the body, an immune system on overdrive, or a combination of reasons. And it's unclear why some children, and not others, are affected. There does seem to be a correlation between COVID severity and the risk of long-term symptoms, according to Stockwell: Kids who are more severely ill with the infection are at greater risk. But, she said, children with mild infections, or even no symptoms at all, can and do develop long COVID. For the current review, Bhutta's team analyzed 31 studies published between December 2019 and December 2022, involving more than 15,000 children and teenagers with confirmed COVID infections. Some studies focused on kids who were ill enough to be hospitalized, but most included those who were sick at home.

Overall, just over 16% of kids had symptoms three months or more after their COVID diagnosis—including problems that had persisted since the infection or newly arose in the weeks to months afterward. The most common symptoms, Bhutta's team found, were persistent sore throat and fevers, fatigue, sleep problems and muscle weakness. But kids—like adults with long COVID—also had an array of other issues, including headaches, shortness of breath and gastrointestinal symptoms like diarrhea and abdominal pain. At this point, Stockwell said, management of long COVID is aimed at easing the particular symptoms a child has. For those kids, and their parents, a major question is, how long will this last? Researchers are still studying the typical course of long COVID. But based on what's known, Bhutta said, at least a portion of kids do get better six to 12 months out. As for what parents can do to protect their kids, it's not yet clear whether COVID vaccination curbs the risk of long COVID should a child become infected. "But," Stockwell said, "we do know that vaccination lowers the risk of severe COVID." That alone is good reason to have your kids vaccinated and up to date on their boosters, Bhutta and Stockwell said. Bhutta also pointed to another major knowledge gap: the lack of studies from middle- and low-income countries. In those countries, with limited access to vaccines and treatments, the prevalence of long COVID among children could actually be higher, Bhutta said.

Original study published (July 21, 2023) in Pediatrics:

https://doi.org/10.1542/peds.2022-060351 

Findings offer insight into biological mechanisms, pointing to possible treatments.  Twelve people with persistent neurological symptoms after SARS-CoV-2 infection were intensely studied at the National Institutes of Health (NIH) and were found to have differences in their immune cell profiles and autonomic dysfunction. These data inform future studies to help explain persistent neurological symptoms in Long COVID. The findings, published in Neurology: Neuroimmunology & Neuroinflammation(link is external), may lead to better diagnoses and new treatments. People with post-acute sequelae of COVID-19 (PASC), which includes Long COVID, have a wide range of symptoms, including fatigue, shortness of breath, fever, headaches, sleep disturbances, and “brain fog,” or cognitive impairment. Such symptoms can last for months or longer after an initial SARS-CoV-2 infection. Fatigue and “brain fog” are among the most common and debilitating symptoms, and likely stem from nervous system dysfunction. Researchers used an approach called deep phenotyping to closely examine the clinical and biological features of Long COVID in 12 people who had long-lasting, disabling neurological symptoms after COVID-19.

Most participants had mild symptoms during their acute infection. At the NIH Clinical Center, participants underwent comprehensive testing, which included a clinical exam, questionnaires, advanced brain imaging, blood and cerebrospinal fluid tests, and autonomic function tests. The results showed that people with Long COVID had lower levels of CD4+ and CD8+ T cells—immune cells involved in coordinating the immune system’s response to viruses—compared to healthy controls. Researchers also found increases in the numbers of B cells and other types of immune cells, suggesting that immune dysregulation may play a role in mediating Long COVID. Consistent with recent studies, people with Long COVID also had problems with their autonomic nervous system, which controls unconscious functions of the body such as breathing, heart rate, and blood pressure. Autonomic testing showed abnormalities in control of vascular tone, heart rate, and blood pressure with a change in posture. More research is needed to determine if these changes are related to fatigue, cognitive difficulties, and other lingering symptoms. Taken together, the findings add to growing evidence that widespread immunological and autonomic nervous system changes may contribute to Long COVID. The results may help researchers better characterize the condition and explore possible therapeutic strategies, such as immunotherapy. The study was supported by the Intramural Research Program at the National Institute of Neurological Disorders and Stroke (NINDS) and is part of an observational study taking place at the NIH Clinical Center designed to characterize changes in the brain and nervous system after COVID-19 (NCT04564287).

Published in Neurology (May 5, 2023):

https://doi.org/10.1212/NXI.0000000000200097 

People who are vaccinated or who take Paxlovid during a Covid-19 infection have a lower risk of developing long Covid, new research shows. The US Centers for Disease Control and Prevention defines long Covid as new, returning or ongoing health issues more than four weeks after an initial infection. According to the CDC, 1 in 5 Covid-19 survivors ages 18 to 64 and 1 in 4 survivors 65 or older have an ongoing health issue that might be attributable to Covid-19 infection. A study published Thursday in JAMA Internal Medicine analyzed data from 41 studies, including more 860,000 people around the world. Of the four studies with vaccination information of nearly 250,000 people, those who had been vaccinated against Covid-19 had almost half the risk of long Covid than people who weren’t vaccinated. “These findings are important because they enable us to better understand who may develop long Covid and also advocate for the benefit of vaccination,” said Dr. Eleana Ntatsaki, a rheumatologist at Ipswich Hospital in England and co-author of the study. Dr. Linda Geng, co-director of Stanford University’s Post-Acute Covid-19 Syndrome Clinic, says the findings are encouraging and add to mounting evidence that vaccines can reduce the risk of long Covid. “That is probably one of the best tools that we have, to get vaccinated to help reduce severe acute illness but helping hopefully also to prevent and protect against developing long Covid,” said Geng, who was not involved in the research. Women, people who smoke, those who are overweight and adults over 40 are more likely to have long Covid, the study found.

Hospitalization during a Covid-19 infection as well as underlying health problems including asthma, COPD, diabetes, coronary heart disease, a weakened immune system, anxiety and depression are also associated with increased risk of the condition. Previous research has found that long Covid is associated with nearly twice the risk of heart and lung problems or death. The study authors say these findings will help providers better understand long Covid and serve those living with the condition. “We can have a better strategy for optimizing any modifiable risk factors, with public health promotion campaigns, encouraging smoking cessation, vaccination and healthy weight management in the target population,” Ntatsaki said. Another study published Thursday in JAMA Internal Medicine found that using the antiviral medication Paxlovid within five days of a positive Covid-19 test was associated with a lower risk of long Covid in all age groups, regardless of vaccination status or history of infection. Paxlovid was linked with a 26% lower risk of long Covid, a 47% lower risk of death and a 24% lower risk of hospitalization 30 days after an initial infection.

Navigational problems and an increased risk of developing prosopagnosia, or face blindness, have been associated with COVID-19 infection. While it’s widely known that COVID-19 can cause a range of neurological problems, including the loss of smell and taste, and impairments in attention, memory, speech, and language, known as “brain fog,” the study is the first to report “prosopagnosia,” also known as face blindness, following symptoms consistent with COVID-19. The researchers worked with Annie, a 28-year-old customer service representative and part-time portrait artist, who was diagnosed with COVID-19 in March 2020 and suffered a symptom relapse two months later. Shortly after the relapse, Annie noticed difficulty with face recognition and navigation. “When I first met Annie, she told me that she was unable to recognize the faces of her family,” says lead author Marie-Luise Kieseler, a graduate student in the department of psychological and brain sciences and member of the Social Perception Lab at Dartmouth. Annie recounted the time when she was at a restaurant meeting her family for the first time after having COVID-19. She didn’t recognize them, and when she walked past them again, her father called out to her. “It was as if my dad’s voice came out of a stranger’s face,” says Annie, who now relies on voices to recognize people that she knows Annie also experienced navigational deficits after having COVID-19. She has had difficulty remembering where particular sections in her grocery store are and relies on Google maps and its pin function to remember where she parks her car. “The combination of prosopagnosia and navigational deficits that Annie had is something that caught our attention because the two deficits often go hand in hand after somebody either has had brain damage or developmental deficits,” says senior author Brad Duchaine, a professor of psychological and brain sciences and principal investigator of the Social Perception Lab at Dartmouth. “That co-occurrence is probably due to the two abilities depending on neighboring brain regions in the temporal lobe.” The research team conducted a series of tests with Annie to evaluate her problems with face recognition and determine whether she also has difficulties with other perceptual or cognitive abilities.

Recognizing familiar and learning the identities of unfamiliar faces was especially challenging for Annie. For one of the tests, Annie was sequentially presented with 60 images of celebrity faces and was asked to name them. Afterward, she was presented with a list of the celebrities featured in the test to see if she knew them. Annie correctly identified 29% of the 48 celebrities whom she was familiar with as compared to most people, who can correctly identify 84% of familiar celebrities. The second test was a doppelganger test. Annie was shown a celebrity’s name and then presented with images of two faces: the face of a celebrity and that of someone similar, and was then asked to identify which face was the famous person. She identified the celebrity in 69% of the 58 trials, as compared to 87% in the control group. Annie’s more limited ability to learn and then recognize unfamiliar faces was demonstrated using the Cambridge Face Memory Test. In the test, participants learn six men’s faces and then they are asked to discriminate between the learned faces and other faces. On average, people are usually able to identify 80% correctly while Annie was only able to identify 56% correctly. “Our results from the test with unfamiliar faces show that it wasn’t just that Annie couldn’t recall the name or biographical information of a famous person that she was familiar with, but she really has trouble learning new identities,” says Kieseler. Her test scores in face detection, face identity perception, and object recognition were normal, indicating respectively, that Annie’s problems with faces are due to face memory deficits and are not a more generalized impairment. Annie had flawless test scores in scene processing. When she was shown a set of landscapes and was then shown them again with a new set, she made no errors in identifying the landscapes she had been previously shown. “It’s likely, therefore, that her navigational impairments result from processes that might contribute to cognitive map representation rather than scene recognition deficits,” says Kieseler. “This sort of dissociation like we’re seeing in Annie is seen in some people who have navigational deficits, where they can recognize where they are but when they’re asked where another place is relative to where they are right now, they struggle,” says Duchaine. “They have trouble understanding relationships between different places, which is a step beyond recognizing the place that you’re in.”

Annie also did really well in voice recognition tests in comparison to the controls, so the researchers think that her problems with face processing are mostly likely due to a deficit within the visual system. “It’s been known that there are broad cognitive problems that can be caused by COVID-19, but here we’re seeing severe and highly selective problems in Annie,” says Duchaine, “and that suggests there might be a lot of other people who have quite severe and selective deficits following COVID.” To determine if other people have experienced perception, recognition, and navigational problems due to long COVID, the research team obtained self-reported data from 54 individuals who had long COVID with symptoms for 12 weeks or more; and 32 persons who had reported that they had fully recovered from COVID-19. Respondents were asked to rate themselves on statements about their visual perception and cognitive functioning, such as whether they could track characters on TV or navigate their environment, before and after they had contracted COVID-19. The research team measured the change in the before-and-after ratings and compared results of the long COVID group to that of the fully recovered COVID group. “Most respondents with long COVID reported that their cognitive and perceptual abilities had decreased since they had COVID, which was not surprising, but what was really fascinating was how many respondents reported deficits,” says Kieseler. “It was not just a small concentration of really impaired cases but a broad majority of people in the long COVID group reported noticeable difficulties doing things that they were able to do before contracting COVID-19 without any problems.” “One of the challenges that many respondents reported was a difficulty with visualizing family and friends, which is something that we often hear from prosopagnosics,” says Duchaine, who is the co-founder of faceblind.org. “Our study highlights the sorts of perceptual problems with face recognition and navigation that can be caused by COVID-19 — it’s something that people should be aware of, especially physicians and other health care professionals.” Duchaine says, “As far as we know, nobody’s measured the sorts of high level, visual processing abilities that are affected by COVID-19 that we focused on here in this paper, so if it’s happening in the visual system, it’s likely that selective deficits due to problems in other brain areas are occurring in some people as well.” Individuals experiencing perceptual or vision problems or navigational difficulties that they think may be caused by COVID-19 are welcome to contact the research team, who hope to do more research in this area. For more information about problems with face recognition such as prosopagnosia (face blindness) and other visual processing difficulties, visit: www.faceblind.org.

Cited research published  (March 9, 2023) in Cortex:

https://doi.org/10.1016/j.cortex.2023.01.012 

Background: Post-acute sequelae of COVID, termed “Long COVID”, is an emerging chronic illness potentially affecting ~10% of those with COVID-19. We sought to determine if outpatient treatment with metformin, ivermectin, or fluvoxamine could prevent Long COVID. 

Methods: COVID-OUT (NCT04510194) was a decentralized, multi-site trial in the United States testing three medications (metformin, ivermectin, fluvoxamine) using a 2x3 parallel treatment factorial randomized assignment to efficiently share placebo controls. Participants, investigators, care providers, and outcomes assessors were masked to randomized treatment assignment. Inclusion criteria included: age 30 to 85 years with overweight or obesity, symptoms <7 days, enrolled within <=3 days of documented SARS-CoV-2 infection. Long COVID diagnosis from a medical provider was a pre-specified secondary outcome assessed by monthly surveys through 300 days after randomization and confirmed in medical records. 

Findings: Of 1323 randomized trial participants, 1125 consented for long-term follow up, and 95.1% completed >9 months of follow up. The median age was 45 years (IQR, 37 to 54), and 56% were female (7% pregnant). The median BMI was 30 kg/m2 (IQR, 27 to 34). Overall, 8.4% reported a medical provider diagnosed them with Long COVID; cumulative incidence: 6.3% with metformin and 10.6% with matched placebo. The hazard ratio (HR) for metformin preventing Long COVID was 0.58 (95%CI, 0.38 to 0.88; P=0·009) versus placebo. The metformin effect was consistent across subgroups, including viral variants. When metformin was started within <4 days of symptom onset, the HR for Long COVID was 0.37 (95%CI, 0.15 to 0.95).  No statistical difference in Long COVID occurred in those randomized to either ivermectin (HR=0.99; 95%CI, 0.59 to 1.64) or fluvoxamine (HR=1.36; 95%CI, 0.78 to 2.34).

Interpretations: A 42% relative decrease and 4.3% absolute decrease in the Long COVID incidence occurred in participants who received early outpatient COVID-19 treatment with metformin compared to exact-matching placebo.

Trial Registration: ClinicalTrials.gov: NCT04510194.

Preprint available at the Lancet (March 6, 2023):

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4375620 

Question  Do post-acute sequelae of SARS-CoV-2 increase risks of 1-year adverse outcomes?

Findings  In this case-control study of 13 435 US adults with post–COVID-19 condition (PCC) and 26 870 matched adults without COVID-19, the adults with PCC experienced increased risks for a number of cardiovascular outcomes, such as ischemic stroke. During the 12-month follow-up period, 2.8% of the individuals with PCC vs 1.2% of the individuals without COVID-19 died, implying an excess death rate of 16.4 per 1000 individuals.

Meaning  Individuals with PCC may be at increased risk for adverse outcomes in the year following initial infection.

Importance  Many individuals experience ongoing symptoms following the onset of COVID-19, characterized as postacute sequelae of SARS-CoV-2 or post–COVID-19 condition (PCC). Less is known about the long-term outcomes for these individuals.

Objective  To quantify 1-year outcomes among individuals meeting a PCC definition compared with a control group of individuals without COVID-19.

Design, Setting, and Participants  This case-control study with a propensity score–matched control group included members of commercial health plans and used national insurance claims data enhanced with laboratory results and mortality data from the Social Security Administration’s Death Master File and Datavant Flatiron data. The study sample consisted of adults meeting a claims-based definition for PCC with a 2:1 matched control cohort of individuals with no evidence of COVID-19 during the time period of April 1, 2020, to July 31, 2021.

Exposures  Individuals experiencing postacute sequelae of SARS-CoV-2 using a Centers for Disease Control and Prevention–based definition.

Main Outcomes and Measures  Adverse outcomes, including cardiovascular and respiratory outcomes and mortality, for individuals with PCC and controls assessed over a 12-month period.

Results  The study population included 13 435 individuals with PCC and 26 870 individuals with no evidence of COVID-19 (mean [SD] age, 51 [15.1] years; 58.4% female). During follow-up, the PCC cohort experienced increased health care utilization for a wide range of adverse outcomes: cardiac arrhythmias (relative risk [RR], 2.35; 95% CI, 2.26-2.45), pulmonary embolism (RR, 3.64; 95% CI, 3.23-3.92), ischemic stroke (RR, 2.17; 95% CI, 1.98-2.52), coronary artery disease (RR, 1.78; 95% CI, 1.70-1.88), heart failure (RR, 1.97; 95% CI, 1.84-2.10), chronic obstructive pulmonary disease (RR, 1.94; 95% CI, 1.88-2.00), and asthma (RR, 1.95; 95% CI, 1.86-2.03). The PCC cohort also experienced increased mortality, as 2.8% of individuals with PCC vs 1.2% of controls died, implying an excess death rate of 16.4 per 1000 individuals.

Conclusions and Relevance  This case-control study leveraged a large commercial insurance database and found increased rates of adverse outcomes over a 1-year period for a PCC cohort surviving the acute phase of illness. The results indicate a need for continued monitoring for at-risk individuals, particularly in the area of cardiovascular and pulmonary management.

Published in JAMA Network (March 3, 2023):

https://doi.org/10.1001/jamahealthforum.2023.0010 

Background: This longitudinal study evaluates the extent of impaired pulmonary function over time after SARS-CoV-2 infection across the full spectrum of COVID-19 severity.

Methods: Pulmonary function was measured by diffusing capacity for carbon monoxide (DLCO) at one, six, and twelve months after illness onset. Additionally, data on sociodemographics, clinical characteristics, symptoms, and health-related quality of life (HRQL) were collected. Pulmonary function and determinants were modelled over time using mixed-effect linear regression. Determinants of pulmonary impairment at 12 months since illness onset were identified using logistic regression.

Findings: Between May 2020 and December 2021, 301 of 349 participants underwent at least one pulmonary function test. After one year of follow-up, 25% of the participants had an impaired pulmonary function which translates in 11%, 22%, and 48% of the participants with mild, moderate and severe/critical COVID-19. Improvement in DLCO among the participants continued over the period across one, six and twelve months. Having more than three comorbidities (p<0·001) and initial severe/critical illness (p<0·001) were associated with slower improvement of pulmonary function over time, adjusted for age and sex. HRQL improved over time and was not different to those without impaired pulmonary function.

Interpretation: The prevalence of impaired pulmonary function after twelve months of follow-up, was still significant among those with initially moderate or severe/critical COVID-19. However, those who continued to have impaired pulmonary function after one year did not have impaired HRQL.

Preprint at the Lancet (Feb. 24, 2023):

 http://dx.doi.org/10.2139/ssrn.4366836

Scientific American is the essential guide to the most awe-inspiring advances in science and technology, explaining how they change our understanding of the world and shape our lives. Tara Ghormley has always been an overachiever. She finished at the top of her class in high school, graduated summa cum laude from college and earned top honors in veterinary school. She went on to complete a rigorous training program and build a successful career as a veterinary internal medicine specialist. But in March 2020 she got infected with the SARS-CoV-2 virus—just the 24th case in the small, coastal central California town she lived in at the time, near the site of an early outbreak in the COVID pandemic. “I could have done without being first at this,” she says. Almost three years after apparently clearing the virus from her body, Ghormley is still suffering. She gets exhausted quickly, her heartbeat suddenly races, and she goes through periods where she can't concentrate or think clearly. Ghormley and her husband, who have relocated to a Los Angeles suburb, once spent their free time visiting their “happiest place on Earth”—Disneyland—but her health prevented that for more than a year. She still spends most of her days off resting in the dark or going to her many doctors' appointments. Her early infection and ongoing symptoms make her one of the first people in the country with “long COVID,” a condition where symptoms persist for at least three months after the infection and can last for years. The syndrome is known by medical professionals as postacute sequelae of COVID-19, or PASC.

People with long COVID have symptoms such as pain, extreme fatigue and “brain fog,” or difficulty concentrating or remembering things. As of February 2022, the syndrome was estimated to affect about 16 million adults in the U.S. and had forced between two million and four million Americans out of the workforce, many of whom have yet to return. Long COVID often arises in otherwise healthy young people, and it can follow even a mild initial infection. The risk appears at least slightly higher in people who were hospitalized for COVID and in older adults (who end up in the hospital more often). Women and those at socioeconomic disadvantage also face higher risk, as do people who smoke, are obese, or have any of an array of health conditions, particularly autoimmune disease. Vaccination appears to reduce the danger but does not entirely prevent long COVID. The most common, persistent and disabling symptoms of long COVID are neurological. Some are easily recognized as brain- or nerve-related: many people experience cognitive dysfunction in the form of difficulty with memory, attention, sleep and mood. Others may seem rooted more in the body than the brain, such as pain and postexertional malaise (PEM), a kind of “energy crash” that people experience after even mild exercise. But those, too, result from nerve dysfunction, often in the autonomic nervous system, which directs our bodies to breathe and digest food and generally runs our organs on autopilot. This so-called dysautonomia can lead to dizziness, a racing heart, high or low blood pressure, and gut disturbances, sometimes leaving people unable to work or even function independently....

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A new study analyzing nearly 2 million patient records in Israel concludes that for most people, the troubling symptoms that persist after a mild Covid infection fade away after about a year. Since long Covid emerged, how best to define it, predict it, and treat it has been up for debate, but perhaps the most urgent question for patients and providers alike has been how long it lasts. A new study analyzing nearly 2 million patient records in Israel concludes that for most people, the troubling symptoms that persist after a mild Covid infection fade away after about a year. Just as estimates of long Covid’s prevalence have varied widely, so have conclusions about a variety of symptoms. Covid infections reach into multiple organ systems, as does long Covid. Scientists have reported on some neuropsychiatric conditions lingering for two years, for example, but the team from the KI Research Institute wanted to paint a broader picture of long Covid’s duration. “When we started this study there was a lot of uncertainty regarding the long-term effects of the pandemic and there was a fear that a large proportion of infected individuals will have long-lasting symptoms and emergence of new morbidities,” the study’s senior author Maytal Bivas-Benita and lead author Barak Mizrahi said in a joint email to STAT. “As we analyzed the data, we were surprised to find only a small number of symptoms that were related to Covid and remained for a year post infection and the low number of people affected by them.” For their paper published Wednesday in BMJ, the researchers analyzed 1,913,234 patient records from Maccabi Healthcare Services, a large health maintenance organization in Israel whose members were tested for Covid-19 from March 2020 to October 2021, when the original virus and the Alpha and Delta variants were circulating. After compiling a list of 70 long Covid symptoms, they looked for them at different time points, comparing the nearly 300,000 patients who tested positive to comparable patients who tested negative for Covid-19, excluding anyone hospitalized for the illness. Studying non-hospitalized patients better reflects the vast majority of people who contract Covid, they said, also making it easier to tease out effects caused by the virus and not by intensive care treatments such as ventilators. “We wanted to truly understand what are the long-term effects of this infection on the majority of the population and whether we should expect a significant burden on healthcare providers,” Bivas-Benita and Mizrahi wrote.

Throughout the year of follow-up, patients with mild Covid-19 had an increased risk of problems including loss of smell and taste, concentration and memory impairment, breathing difficulties, weakness, palpitations, strep throat, and dizziness. Later in the year, health records showed more hair loss (particularly among women), chest pain, cough, muscle aches and pains, and respiratory disorders among Covid patients. But for most people, these problems also cleared up by the end of one year. Vaccinated people were at lower risk of developing breathing difficulties after breakthrough infections — the most common problem after mild infection, along with weakness — compared with unvaccinated people, but their risk was similar for other conditions. People from 41 to 60 years old had more health problems than people in other age groups, and shortness of breath continued to be a problem for those over 60. Children had fewer long Covid symptoms than adults, and most of those issues were gone after a year. “This is a reassuring large population medical record study,” Michael Absoud, honorary reader in the Department of Women & Children’s Health at King’s College London and not involved in the study, said. “It confirms that in children, of the small proportion who have prolonged persistent symptoms post SARS-CoV-2 infection, the vast majority show a very good recovery.” There were minor differences between men’s and women’s risk of outcomes, and findings remained consistent across the SARS-CoV-2 variants that emerged before Omicron. “The general message that symptoms improve over time is encouraging, but it may take a year or so for some symptoms to resolve,” Peter Openshaw, a professor of experimental medicine at Imperial College London, said. He was not involved in the research. “The study adds to the evidence that outcomes are improved by vaccination, even if vaccines don’t prevent viral transmission very well.” Ziyad Al-Aly, clinical epidemiologist at Washington University in St. Louis, isn’t so sure.

He thinks the study’s message may be too optimistic, owing to its design. Comparing people who test positive to people who test negative may not account for the reason people are taking Covid tests. Someone with cancer might need to test before starting chemotherapy, he said, or someone else might need surgery for another reason. “Better designs would be needed to more confidently elevate our understanding, to actually deepen our understanding of the the toll and scale of the condition and the trajectory of the health performance of the individual affected with long Covid over the the ensuing year after that infection,” Al-Aly, who is also chief of research and development at the VA St. Louis Health Care System, told STAT. He was not part of the study. “It doesn’t mean that some people are not improving. We see a big improvement in some individuals …. I wish this was normally the case, but it’s really too rosy to be true.” In response, the study authors said it’s important to remember that PCR tests to detect Covid-19 were offered to all Israeli citizens free of charge, without needing a referral, throughout the entire study period. That meant 76% of Maccabi Healthcare Services’ members took at least one PCR test during the study period. And they say “chances are minimal” that those test-negative patients would be more likely to have symptoms like long Covid because any chronic conditions they had at baseline were matched to test-positive patients who also had them. And, they pointed out, infectious diseases other than Covid were rare during social distancing and lockdown in effect during the study period. The researchers acknowledged that not everyone recovers. And their results come from one country. “We are not claiming there are no patients who suffer from long Covid symptoms (like dyspnea, weakness, cognitive impairment etc.),” they wrote in a follow-up email. “This does not contradict evidence that a small number of patients do suffer from long lasting symptoms as seen in this analysis.” Next on their research agenda: evaluating the effects of the Omicron strain and assessing the prevalence and severity of outcomes following reinfections.

Study cited published in BMJ (Jan. 11, 2023):

 https://doi.org/10.1136/bmj-2022-072529 

A picture is emerging of the toll long Covid takes inside the body and why it can be so debilitating. Millions of people continue to suffer from exhaustion, cognitive problems and other long-lasting symptoms after a coronavirus infection. The exact causes of the illness, known as long Covid, are not known. But new research offers clues, describing the toll the illness takes on the body and why it can be so debilitating.

Diagnosing Long Covid

Patients with severe Covid may wind up in hospitals or on ventilators until their symptoms resolve. Damage to the body from severe Covid — pneumonia, low oxygen, inflammation — typically shows up on traditional diagnostic tests. Long Covid is different: A chronic illness with a wide variety of symptoms, many of which are not explainable using conventional lab tests. Difficulties in detecting the illness have led some doctors to dismiss patients, or to misdiagnose their symptoms as psychosomatic. But researchers looking more deeply at long Covid patients have found visible dysfunction throughout the body. Studies estimate that perhaps 10 to 30 percent of people infected with the coronavirus may develop long-term symptoms. It’s unclear why some people develop long Covid and others don’t, but four factors appear to increase the risk: high levels of viral RNA early during an infection, the presence of certain autoantibodies, the reactivation of Epstein-Barr virus and having Type 2 diabetes.

The Immune System

“Dang, why am I always so sick?” — Messiah Rodriguez, 17

Long Covid patients appear to have disrupted immune systems compared to post-Covid patients who fully recover. Many researchers believe chronic immune dysfunction after a coronavirus infection may set off a chain of symptoms throughout the body. One possibility is that the body is still fighting remnants of the coronavirus. Researchers found that the virus spreads widely during an initial infection, and that viral genetic material can remain embedded in tissues — in the intestines, lymph nodes and elsewhere — for many months. Ongoing studies are trying to determine if these viral reservoirs cause inflammation in surrounding tissues, which could lead to brain fog, gastrointestinal problems and other symptoms. Researchers have also found evidence that Covid may trigger a lasting and damaging autoimmune response. Studies have found surprisingly high levels of autoantibodies, which mistakenly attack a patient’s own tissues, many months after an initial infection. A third possibility is that the initial viral infection triggers chronic inflammation, possibly by reactivating other viruses in the patient’s body that are normally dormant. The reactivation of Epstein-Barr virus, which infects most people when they are young, might help predict whether a person will develop long Covid, one study found. Inside the intricate world of the immune system, these explanations may coexist. And just as different long Covid patients may have different symptoms, they may also have different immune problems, too. Identifying the problems that are central to each patient’s illness will be critical for guiding treatment, said Dr. Akiko Iwasaki, an immunologist at Yale. For instance, a patient with autoantibodies might benefit from immunosuppressive medication, while a patient with remnants of the Covid virus should receive antivirals, Dr. Iwasaki said. “Depending on what each person has, the treatment would be quite different.”.....