Researchers at Vanderbilt University Medical Center have isolated human monoclonal antibodies against influenza B, a significant public health threat that disproportionately affects children, the elderly and other immunocompromised individuals.
Seasonal flu vaccines cover influenza B and the more common influenza A but do not stimulate the broadest possible range of immune responses against both viruses. In addition, people whose immune systems have been weakened by age or illness may not respond effectively to the flu shot.
Small-molecule drugs that block neuraminidase, a major surface glycoprotein of the influenza virus, can help treat early infection, but they provide limited benefit when the infection is more severe, and they are generally less effective in treating influenza B infections. Thus, another way to combat this virus is needed.
Reporting in the journal Immunity, the VUMC researchers describe how, from the bone marrow of an individual previously vaccinated against influenza, they isolated two groups of monoclonal antibodies that bound to distinct parts of the neuraminidase glycoprotein on the surface of influenza B.
One of the antibodies, FluB-400, broadly inhibited virus replication in laboratory cultures of human respiratory epithelial cells. It also protected against influenza B in animal models when given by injection or through the nostrils.
Intranasal antibody administration may be more effective and have fewer systemic side effects than more typical routes -; intravenous infusion or intramuscular injection -; in part because intranasal antibodies may "trap" the virus in the nasal mucus, thereby preventing infection of the underlying epithelial surface, the researchers suggested.
These findings support the development of FluB-400 for the prevention and treatment of influenza B and will help guide efforts to develop a universal influenza vaccine, they said.
Antibodies increasingly have become an interesting medical tool to prevent or treat viral infections. We set out to find antibodies for the type B influenza virus, which continues to be a medical problem, and we were happy to find such especially powerful molecules in our search."
James Crowe Jr., MD.,paper's corresponding author
Crowe, who holds the Ann Scott Carell Chair, is University Distinguished Professor of Pediatrics and director of the Vanderbilt Vaccine Center, which has isolated monoclonal antibodies against a host of viral infections, including COVID-19.
The paper's first author, Rachael Wolters, DVM, PhD, is a former graduate student in the Crowe lab. Other VUMC co-authors are Elaine Chen, PhD, Ty Sornberger, Luke Myers, Laura Handal, Taylor Engdahl, Nurgen Kose, Lauren Williamson, PhD, Buddy Creech, MD, and Katherine Gibson-Corley, DVM, PhD.
This study was supported in part by National Institutes of Health grants T32AI112541, K01OD036063 and U01AI150739, NIH-HHS contracts 75N93019C00074 and 75N93019C00073, and the Collaborative Influenza Vaccine Innovation Centers program of the National Institute of Allergy and Infectious Diseases.
Source:
Journal reference:
Wolters, R. M., et al. (2024). Isolation of human antibodies against influenza B neuraminidase and mechanisms of protection at the airway interface.Immunity. doi.org/10.1016/j.immuni.2024.05.002.
Australia appears to be experiencing a re-emergence of the infectious disease mpox, formerly called monkeypox.
Some 40 cases have been recorded so far in 2024, already surpassing the total number recorded for 2023 (26). Victoria has reported 24 cases this year, while Queensland saw ten cases reported in May.
There was previously a significant mpox outbreak in 2022, with a total of 144 cases across Australia. All cases since 2022 have been in males, most commonly those aged 30 to 39. Mpox cases are on the rise elsewhere, too.
So what is mpox? And is there a vaccine available? Heres what to know about this virus.
Mpox belongs to the orthopoxvirus family, which is also responsible for smallpox.
Symptoms include fever and rash, typically starting on the hands, feet and face. The genitals may also be affected. The rash is infectious until the lesions have scabbed over.
There are two clades, or varieties, of mpox: clade I and clade II. Up to 10% of people infected with clade I may die, compared to 1% or less of those infected with clade II.
Traditionally, both clades of mpox have been endemic in countries in central and western Africa, where it transmits from animals to humans, and has occasionally caused human outbreaks.
Mpox outbreaks began occurring outside Africa in 2018, with cases detected in the United Kingdom, Israel and Singapore in people travelling from Nigeria, which began experiencing outbreaks in 2017.
The 2022 epidemic spread to non-endemic regions such as Europe, the Americas, and Australia, with more than 97,000 cases confirmed globally to date.
These outbreaks were caused by clade IIb, a variant of clade II, with case fatality below 1%. Clade IIb is also behind the current cases in Australia.
Recent research indicates both clades of mpox are undergoing rapid mutations, with genetic changes in clade I that may enhance its transmissibility among humans.
These mutations suggest a shift from its historical zoonotic transmission patterns toward sustained human-to-human spread.
Mpox spreads between people primarily through close contact with infected lesions or bodily fluids. Sexual transmission accounts for most of clade IIbs spread, especially among high-risk groups like gay, bisexual, and other men who have sex with men.
The pattern of spread appears different for the two clades. Like smallpox, mpox is a respiratory virus and has been found in ambient air, so respiratory transmission is possible.
Clade I is causing large epidemics in the Democratic Republic of Congo (DRC), with more than 20,000 suspected cases since 2023.
The estimated fatality rate in DRC is 4.6%, with 70% of cases and close to 90% of deaths in children under 15.
This suggests respiratory and close-contact transmission are the primary modes of spread in DRC. However, sexual transmission of clade I has also been reported.
The primary strategy for preventing further outbreaks of mpox in Australia is vaccination. The recommended shot is the JYNNEOS vaccine, which was developed as a smallpox vaccine.
Older smallpox vaccines are made from a live virus called vaccinia, a related orthopoxvirus that protects against smallpox and mpox. The older vaccines have fully replicating vaccinia virus in them, which can be risky for people with weakened immune systems. The JYNNEOS vaccine is modified so the vaccinia virus doesnt replicate in the body and is safer for people with conditions such as HIV.
For full protection, two doses are required at least 28 days apart. Two doses given before exposure to the virus is 84% effective in preventing mpox and protection is believed to last for at least a couple of years.
Cases may still occur in people who are vaccinated, but these infections are typically milder.
The vaccine is also effective after exposure to the virus, but less so than if its given beforehand.
Australian guidelines recommend vaccination in gay, bisexual, and other men who have sex with men. They also recommend vaccination for sex workers, and people with HIV who may be at risk of exposure to mpox.
Health-care workers who treat or are likely to treat patients with mpox are advised to consider having the vaccine.
Post-exposure vaccination is recommended for people who public health authorities classify as having had a high-risk mpox contact in the previous 14 days.
Australias approach to the 2022 mpox outbreak involved ensuring early access to vaccination and working closely with LGBTQ+ community and health organisations. These organisations raised awareness of mpox symptoms, modes of transmission, and vaccination.
In 2023, 48% of gay and bisexual men in Sydney and Melbourne reported having received at least one dose of mpox vaccine. Rapid uptake of vaccines may have contributed to low rates of mpox in Australia.
It appears mpox has become established as a sexually transmitted infection in gay, bisexual, and other men who have sex with men. Achieving and maintaining high rates of vaccination in this group will be crucial in long-term prevention efforts.
Ongoing surveillance is also important, while contact tracing will help minimise the size of any clusters, facilitating post-exposure vaccination where warranted. In Australia, state and territory health departments have extensive experience in contact tracing and work with affected communities.
Australia has so far been successful in avoiding a major epidemic, including in early 2023 when Sydney WorldPride brought thousands of gay men from around the world to Sydney.
In the next few years, unequal access to vaccination around the world will likely mean continued introductions of mpox from settings with lower vaccination rates. Ensuring equitable vaccine access is vital to global and local disease control.
A global approach to controlling mpox is essential, as infections in one country can spread rapidly internationally, as the 2022 epidemic showed.
Early in the COVID-19 pandemic, some states allowed COVID-19 patients to be discharged from hospitals to skilled nursing facilities (SNFs), and even offered financial incentives to SNFs to take in patients to deal with hospital bed shortages.
"The potential human cost of these policies continues to be controversial," the authors wrote. "Some observers have argued that the policies had little impact, while other observers have blamed admissions for seeding or worsening COVID-19 outbreaks in SNFs."
The potential human cost of these policies continues to be controversial
Now a study in JAMA Internal Medicine shows this practice led to preventable COVID-19 cases in the SNFs and increased death rates. Furthermore, SNFs that reported staff and personal protective equipment (PPE) shortages saw bigger increases in COVID-19 morbidity and mortality.
The study was conducted by comparing matched groupings of 264 SNFs with initial admission of COVID-19positive patients (exposed facilities) and 518 comparator SNFs without initial admission (control facilities) from June 2020 to March 2021. Outcomes were assessed during a 15-week follow-up period.
The authors found that exposed SNFs had a cumulative increase of 6.94 (95% confidence interval [CI], 2.91 to 10.98) additional COVID-19 cases per 100 residents compared with control SNFs, a 31.3% increase.
Exposed facilities saw 2.31 (95% CI, 1.39-3.24) additional cumulative COVID-19related deaths per 100 residents compared with control facilities, representing a 72.4% increase compared with the sample mean (SD) of 3.19.
The authors defined PPE shortage as less than a 7-day supply of N95 respirators or surgical masks. Facilities with PPE shortages had an additional 14.81 [95% CI, 2.38 to 27.25] cases per 100 residents compared with those without such shortages.
In an invited commentary, James S. Goodwin, MD, and Huiwen Xu, PhD, said the findings of the study should result in outrage. Even in the earliest days of the pandemic, state public health leaders knew SNFs were unprepared to quarantine patients with COVID-19, they said, with inadequate staff, space, PPE, training, and protocols.
Also the earliest and deadliest outbreaks in the United States were occurring in nursing facilities, they wrote. In the first months of the pandemic, half of the nation's deaths occurred in nursing homes, even though they housed only 0.4% of US citizens.
"To the question, 'What else could we have done?' the answer is anything but this, anything but a move that fed the flames of the pandemic, creating more infections, more hospitalizations, and more deaths," Goodwin and Xu wrote.
Today a new report from the National Academies of Sciences, Engineering, and Medicine presents a number of conclusions about long-COVID diagnosis, symptoms, and impact on daily function, including that the condition can cause more than 200 symptoms, and that a positive COVID-19 test is not necessary to make a long-COVID diagnosis.
The findings are meant to guide the Social Security Administration (SSA) and are published one week before the National Academies of Sciences, Engineering, and Medicine is set to offer a new single definition of long COVID that can be used across US governmental groups as a way to streamline treating the condition in the years to come.
"This report offers a comprehensive review of the evidence base for how Long COVID may impact a patient's ability to engage in normal activities, such as going to work, attending school, or taking care of their families," said Victor J. Dzau, MD, president of the National Academy of Medicine, in a National Academies press release. "Its findings will be useful to anyone attempting to understand how Long COVID may affect the millions of people in the U.S. who have reported symptoms."
According to the Centers for Disease Control and Prevention, 5.3% of Americans currently have long COVID, with a significant proportion of those experiencing disability from the condition.
In today's report, more than 200 symptoms are formally listed as possible signs of long COVID, affecting every organ system. Women are twice as likely to men to experience long COVID, but people who have never received a diagnosis or even a positive COVID-19 test may be experiencing symptoms of the condition.
Though people with mild or even asymptomatic cases of acute COVID can develop long COVID, the report recognizes that people whose infection required hospitalization are two to three times more likely to experience long COVID than are those who were not hospitalized.
Emphasized throughout the report is the similarity long COVID has to other chronic conditions, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia, and postural orthostatic tachycardia syndrome (POTS).
Like those conditions there is no current way to treat long COVID, though long COVID does have a better prognosis than does ME/CFS.
While there is evidence that many people with Long COVID symptoms have improved by 12 months, data beyond that time frame is limited but suggestive that recovery might plateau.
"While there is evidence that many people with Long COVID symptoms have improved by 12 months, data beyond that time frame is limited but suggestive that recovery might plateau or progress at a slower rate," the authors wrote.
Children and teens with long COVID are also more likely than adults are to make a full recovery.
Long COVID can impair a person's ability to work or attend school for 6 months to 2 years or more after COVID-19 infection, the authors said.
Disability from long COVID is associated with acute disease severity, female sex, and baseline comorbidities, the authors said. Though some people with long COVID applying for disability with the SSA will qualify under the SSA's current listing of impairments, many will not.
"Three frequently reported health effects that can significantly interfere with the ability to perform work or school activities and may not be captured in the SSA Listings are chronic fatigue and post-exertional malaise, post-COVID-19 cognitive impairment, and autonomic dysfunction, all of which can be difficult to assess clinically in terms of their severity and effects on a persons functioning," the authors said.
Whats the issue?
Following the peak of the COVID-19 pandemic, researchers continue to investigate the factors related to the spread of diseaseand how city leaders can better respond before, during, and after such crises. Housing conditions, for example, can play a role in infectious disease risk. Substandard housingwhich might feature poor ventilation, overcrowding, and dampnesscan create an environment favorable to respiratory disease.
So, did poor housing conditions lead to moreand more severecases of COVID-19 infection during the pandemic?
Researchers from the Bloomberg Center for Cities at Harvard University and the MGH Institute of Health Professions studied the connections between poor housing conditions and COVID-19 infection and severity during the first year of the pandemic. They combined city housing data with healthcare data for residents of Chelsea, Massachusettsa densely populated city with high levels of substandard housing.
The researchers found that:
They conclude, The results demonstrate the value of combining cross-sector datasets to yield new insights and solutions. Existing city data can be leveraged to identify and prioritize 1) high-risk areas for future pandemic response activities, and 2) for longer-term solutions that address social determinants of health through safe and affordable housing.
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The Class of 2024 had a normal senior year with in-person classes, prom, and graduation.
But this years seniors started high school in fall of 2020 anything but normally. Classes were virtual, they had lunch at home, and they didnt get a chance to make friends when COVID-19 kept school buildings closed.
Chalkbeat spoke to 10 graduating seniors about what it was like to start high school during the pandemic. The Class of 2024 didnt have the usual hallmarks of freshman year like getting lost on the first day of school while trying to find classes, meeting new teachers for the first time, or the awkwardness of making new friends, all while going through the awfulness of puberty.
Even though these graduating seniors had a rocky start, they were resilient. Many students took Advanced Placement classes, dual-credit courses, and participated in many extracurricular activities.
Chicago Public Schools announced in a press release that this years graduating class received over 84,000 acceptance letters from institutions like Northwestern, Howard, and Harvard universities. Over 140 students have already earned associate degrees, more than 2,200 students are graduating from International Baccalaureate programs, and students took more than 49,000 Advanced Placement exams as of May 21, according to the press release.
But the Class of 2024 is also graduating during a contentious time in history. In November, the Chicago Board of Education will transition from an all-appointed board to a hybrid school board with some elected members and some appointed. In the United States, the country will once again vote for president, choosing between incumbent Joseph Biden, a Democrat, and the presumptive Republican candidate, former President Donald Trump, who has been convicted on 34 felony counts of falsifying financial documents. Across the country, college students are protesting the Israel-Hamas War, which has seen over 35,000 Palestinians killed after Hamas killed over 1,000 Israeli citizens during the October 7 attack.
In their own words, Chicagos high school seniors talk about their time in high school, post-secondary education plans, and how they feel about graduating during a presidential election and conflicts happening around the globe.
These interviews have been lightly edited for clarity and length.
Chase Jones, Gwendolyn Brooks College Preparatory Academy, plans to attend Yale University to study biology.
My mother and my eighth grade history teacher, Miss Clark. Brooks is an academic center, so Ive been there since seventh grade. Ive had Miss Clark as my history teacher for eighth grade, ninth grade and 11th grade. She single-handedly has been my support for helping me maintain balance academically. My mother has always been there to support me mentally, socially, and emotionally.
Xamiya Walton, Butler College Prep, a Noble school, will attend Northwestern University on a basketball scholarship to major in journalism with a minor in statistics toward a career as a sports journalist.
I would definitely say my parents and my sisters. Without them I wouldnt have been able to accomplish all the things I did and be where I am now.
Fernando Gonzalez, Marine Leadership Academy, will attend Stanford University and plans to major in computer science and cybersecurity.
It was hard to meet new people through a computer and I struggled in class. I wasnt challenging myself in class. I asked to be switched to AP classes during my freshman year. At first, the administration was hesitant about it because I didnt take any pre-courses to get into AP courses, but they made an exception. I worked so hard with these AP courses, but I still struggled because working through the computer made me feel like I wasnt in the class. I feel like I was in my room the whole time. When we went to lunch, I was like, Okay, Im gonna shut my computer off and lay down.
Raymarreon Polk, Crane Medical Prep High School, will attend DePauw University in the fall and plans to major in computer science.
For me, starting high school during COVID was a little weird. You cant really see many peoples faces because they rarely turned their cameras on, so the teacher saw a bunch of pictures. Also, nobody was really collaborative, because it was so awkward.
Melina Sandoval, Carl Schurz High School, will attend North Park University where she will pursue elementary education.
I had a lot of great opportunities. One of them was meeting the mayor. Another one was when my art teacher, some friends, and I were in class having fun and eating. That was a great memory and I wish I could go back to it. Also, I went to prom. I won duchess but I didnt win queen. It was a good experience still.
Andrew Espinoza, North-Grand High School, will attend Harold Washington College in the fall.
When we came back to school after virtual learning during COVID and seeing friends. It was a great moment because I saw all the people who were on the computer in person.
Guadalupe Miranda, Advantage Academy of DeVry University, will attend Stanford University in the fall to study human biology on a pre-med track.
With the upcoming election, its really nerve-wracking because its the first time for those of us who are 18. It was my first time voting in the primaries. When it comes to things happening in other countries, its really sad and devastating. But seeing how young people are getting involved and using their voice to try to make an impact gives me hope. I hope that young people can continue to use their voices.
Nyla Jackson, Gwendolyn Brooks College Preparatory Academy, will attend Illinois State University and plans to major in marketing analytics.
I hope that the Class of 2024 continues to break barriers and push through in the face of adversity.
Jayveon Edmonds, Al Raby High School for Community and Environment, will head to Southern Illinois University-Carbondale this fall to study zoology.
I didnt feel like my school set me up for greatness. I feel like our creativity was taken away because we didnt have many options and we were underpopulated. My graduating class was only about 20. My school didnt have funding to bring in new teachers or different sports programs. My high school experience was mediocre because of the lack of opportunity. Luckily, I was able to take college classes because I was able to network. But when I talked to other high school students, I realized that we didnt have a lot of options for classes. CPS should have more ways for students to be creative and check on the students in underpopulated schools.
Duchara Moody, Morgan Park High School, will attend the University Of Illinois Urbana - Champaign in the fall and major in secondary education.
What I would like to change or improve about Chicago Public Schools is the teachers. I feel we need more motivating, encouraging, and respectful teachers. I have had different experiences with teachers and noticed that some teachers arent doing their job, especially once I got in high school. I noticed some teachers just dont care and are only there for the pay. This is why I plan to make a difference and become a teacher. Teaching will be such a joyful moment for me and Ill be the best teacher ever. My goal is to instill as much wisdom as I can into kids, be a safe space for them if they need someone to talk to, be the one to cheer them up and let them know that they are the future and that they can be bright.
Samantha Smylie is the state education reporter for Chalkbeat Chicago covering school districts across the state, legislation, special education and the state board of education. Contact Samantha at ssmylie@chalkbeat.org.
Remember the rush to get a COVID-19 shot when the vaccines first arrived? Hundreds of millions of people rolled up their sleeves and got jabbed to protect themselves and others from the virus.
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Today, of course, the pandemic is over, but COVID-19 continues to circulate and infect people around the world. Its not gone.
Thats why being up to date on COVID-19 vaccinations remains a global health priority, says infectious disease specialist Kristin Englund, MD. Heres what you need to be considered fully vaccinated for COVID-19.
COVID-19 continues to evolve with new variants and subvariants emerging. Dozens of different strains have been reported since 2020. Today, omicron and its offshoots are the predominant variants circulating.
As the virus goes through these changes, your bodys defense against these new attackers needs to be reinforced. Mutations to the virus go well beyond what the initial vaccines covered, says Dr. Englund.
Thats why the U.S. Centers for Disease Control and Prevention (CDC) recommends getting an updated 20232024 COVID-19 vaccine to better protect yourself against newer variants and serious illness.
Three updated 20232024 vaccines are available: Pfizer-BioNTech, Moderna and Novavax.
COVID-19 vaccination guidance from the CDC varies by a persons age, vaccination record and health condition. Heres a rundown:
Recommendations for this age group are:
One updated Moderna or Pfizer-BioNTech vaccine is recommended for children in this age group who are either unvaccinated or previously got a vaccine before September 12, 2023.
Recommendations for this age group are:
For this age group, an additional dose of any updated COVID-19 vaccine is recommended at least four months following the first updated dose.
Those who are moderately or severely immunocompromised may benefit from additional doses of an updated COVID-19 vaccine. Talk to your healthcare provider about your specific timing needs.
Vaccines train your immune system to recognize and destroy harmful invaders (such as COVID-19). They teach your body to protect itself by giving intel on potential threats. (Basically, its a biological cheat sheet.)
It takes about two weeks after getting a COVID-19 vaccination for your body to build up immunity against the virus, says Dr. Englund. After that, youre considered fully vaccinated against COVID-19.
Data from the CDC shows the effectiveness of COVID-19 vaccines. A 2024 report shows that people who received an updated vaccine were 54% less likely to get COVID-19. (The findings focus on the four months from mid-September 2023 to January 2024.)
But that protective power naturally declines over time. Dr. Englund says COVID-19 vaccines generally hold firm against the virus for about a year. After that, the shielding effect loses some oomph.
New COVID-19 variants also can lessen the effectiveness of vaccines over time.
As the virus mutates and changes the vaccine loses some of its efficacy in addition to waning over time, explains Dr. Englund. Getting an updated vaccine is important to protect yourself and those around you.
Getting COVID-19 also educates your immune system on the virus and offers some security against future infection. But like vaccines, that immunity lessens over time and doesnt cover new variants.
The CDC recommends getting an updated COVID-19 vaccine even if you have had the virus. (The suggested wait time is 90 days after infection.)
Research shows that people who dont get vaccinated after recovering from COVID-19 are more likely to get reinfected than those who get an updated vaccine to boost their natural immunity.
More than 98% of the population in the United States has some protective immunity against COVID-19 through vaccination, prior infection or some combination of the two, according to the CDC.
But CDC data shows that a much smaller percentage has received an updated COVID-19 vaccine.
Looking ahead, Dr. Englund envisions vaccination against COVID-19 following a similar pattern as whats done for influenza (aka, the flu). In other words, an annual shot to guard against infection and serious illness.
Theres even work underway on a combined flu/COVID-19 vaccine.
This all falls under the concept of public health, says Dr. Englund. Getting vaccinated is part of our moral obligation to make sure were doing everything we can to lower the spread of these viruses and protect those around us.
In the present study, we conducted a comprehensive cross-sectional and longitudinal assessment of individuals with PACS regarding their cognition, mental health status, neuroimaging, and fluid biomarker profile. This approach offers a broad view of PACS patients, which is particularly valuable considering the limited previous research in this area. We evaluated PACS patients with subjective cognitive complaints and their evolution over a 6-month period. Our findings revealed cognitive impairment affecting executive function in more than two-thirds of participants and verbal memory in over one-third. Additionally, prevalent mental health issues included apathy (64%), moderate-severe anxiety (57%), and severe fatigue (35%). Visual memory impairment correlated with total gray matter and subcortical gray matter volume, as well as regional GM reductions in the hippocampus and thalamus. Notably, markers of neuronal damage and inflammation were within normal limits. Importantly, overall health and cognitive evaluations showed no significant change over time. Furthermore, altered executive function and verbal memory, common in PACS, persisted in most subjects without any link to alterations in their biomarker and imaging profiles.
Our study stands out for three main reasons: First, it assesses cognitive deficits through comprehensive neuropsychological evaluations. Whereas the literature on PACS is replete with studies on cognition using screening tools like the Mini-Mental State Examination or the Montreal Cognitive Assessment53,54, our research incorporates detailed neuropsychological evaluations conducted by an experienced neuropsychologist. Second, our study is distinguished by its longitudinal design. Beyond describing the alterations in patients suffering from PACS, we repeated the same analyses six months later to assess their progression and track the evolution of these key health indicators over time. Third, our study is notable for the breadth of areas evaluated: it meticulously examines cognition, mental health, brain structure, and markers of inflammation and neuronal damage concurrently, tracking their longitudinal evolution.
Cognitive evaluations in PACS showed that attention-executive and verbal memory were the most affected domains (Fig.1), which has been described in previous published works; however, the pattern of alterations was broader and more heterogeneous between patients4,5,6,7,52,53. The sample had a high premorbid intelligence and would not be expected to perform below average on cognitive testing. Despite their cognitive reserve, known as a protective mechanism against neurological impairments, these individuals nonetheless experience cognitive deficits. This would likely lead to difficulties in effectively managing daily work and life responsibilities, adversely affecting their quality of life. At a 6-month follow-up, we determined that only the FCSRTDelayed Free Recall of verbal memory scores improved significantly from baseline, using LME models. Nevertheless, if we consider the percentage of normal evaluations (defined as the proportion of tests within clinical limits of normality), there was a significant improvement with time. Considering that most participants with abnormal results were close to the threshold for normal performance, even a slight improvement in these tests could lead to reaching normal threshold values. The improvement in verbal memory and the achievement of normality in the neuropsychological tests indicate a positive trajectory toward normal cognitive functioning. Conversely, high levels of anxiety, apathy, and fatigue present at the beginning of the study remained unchanged. The slight improvements observed in cognition did not strongly affect participants' clinical outcomes or quality of life. It is plausible that the persistence of executive function deficits, ongoing psychological symptoms, and chronic fatigue significantly influenced the overall lack of enhancement in participants' well-being.
Our results are in line with previous published works showing both improvements and persisting cognitive deficits in PACS55,56. Previous research has also documented a decline in executive functions among participants who initially presented with severe cognitive impairment57. The repeated administration of a cognitive test four times over a six-month period in our study raises concerns about the potential influence of a learning effect on the results. To mitigate the learning effect, participants received standardized instructions and practice trials during the baseline assessment to familiarize themselves with the cognitive test procedures, potentially minimizing the influence of initial unfamiliarity or anxiety on test performance. In future research, it is advisable to schedule evaluations at more significant intervals to allow for a more comprehensive study of PACS.
Participants also reported depressive symptoms, anxiety, apathy, fatigue, and low scores in general health. These symptoms did not improve during this 6-month study (Table 2). Given that our analysis demonstrated a significant relationship between one memory test and stratification in anxiety scores, we believe that the coexistence of cognitive and mental health symptoms could not be interpreted as causality. Additionally, the modest sample size in our study may have limited our ability to detect subtle differences in other categories. Recent literature has reported mixed findings regarding the associations between psychiatric comorbidities and cognitive impairment in individuals with PACS. For instance, one recent study identified a significant association between depression symptom severity and cognitive impairment severity among PACS patients58, while findings for post-traumatic stress disorder and anxiety were inconclusive. Conversely, another study found no association between depression, anxiety, total general health status, fatigue, and cognitive profiles59.
In our study of PACS participants, we observed a complex interplay between cognitive and mental health symptoms, with prevalent cognitive impairment alongside high levels of anxiety, apathy, and fatigue. This underscores the intertwined nature of cognitive and mental health domains in PACS, where cognitive deficits may coexist with psychiatric symptoms. We next sought to stratify participants by levels of anxiety, depression, apathy, fatigue, or quality of life scores according to their questionnaire scores. Participants displaying moderate or severe anxiety showed lower results in the ROCFT Recall subtest (adjusted p-value=0.0014). No significant differences were observed in cognitive tests between participants with normal and abnormal values of the other stratification categories. No associations were detected between longitudinal changes in cognitive and mental health measures. Conversely, a previously published work found that changes in executive functions were significantly associated with changes in depressive symptoms57.
While we can hypothesize that mental health issues may impede cognitive symptom improvement, it is worth noting that these mental health issues could be a consequence of the cognitive impairment as described elsewhere60. Understanding this relationship is crucial for informing treatment approaches; interventions targeting cognitive rehabilitation should consider the impact of comorbid psychiatric symptoms. Integrated interventions addressing both cognitive and psychiatric symptoms concurrently may optimize patient outcomes in PACS. Furthermore, both types of symptoms may be influenced by fatigue, which was nearly universal and severe in 35% of participants.
Fatigue has been implicated in various aspects of cognitive function, including attention, processing speed, and executive function, and has been associated with cognitive impairment in other medical conditions such as fibromyalgia and chronic fatigue syndrome. Moreover, fatigue often coexists with psychiatric symptoms such as anxiety and depression, contributing to the complex interplay between cognitive and mental health domains. In a recent study by Delgado-Alonso et al.61 investigated the relationship between subjective cognitive complaints, cognitive function, fatigue, and neuropsychiatric symptoms using various analytical methods. The study found that fatigue played a central role as the main mediator between objective and subjective cognition, while the impact of depression was indirect and mediated through fatigue. The lack of symptom improvement in PACS during the study suggests complex underlying factors. Possible reasons include the chronic nature of PACS, ongoing inflammation, and the interplay between cognitive and mental health symptoms. This highlights the need for personalized, multidisciplinary treatment approaches. Strategies may include pharmacological interventions, cognitive rehabilitation, psychotherapy, and lifestyle modifications.
Our study revealed a specific connection between cognitive deficits and brain changes in individuals with PACS. The ROCFT Recall test, a measure of memory and visual-spatial abilities, was the only cognitive test that showed abnormalities. These abnormalities were connected to both overall and specific areas of brain volume loss, specifically in the GM and WM globally, and in particular regions like the hippocampus and thalamus. This finding is significant because it identifies a direct relationship between certain cognitive deficits and changes in brain structure among individuals with PACS. The fact that these links were observed globally in GM and WM volumes, as well as in specific regions critical for memory and cognition (the hippocampus and thalamus), underscores the potential impact of COVID-19 on brain health. However, the fact that these associations were limited to certain brain regions and were only detected with the ROCFT Recall test suggests that the structural brain changes in PACS might be more nuanced than previously understood. While other studies, such as the one by Dez-Ciranda et al.5, have also found connections between cognitive deficits and MRI results, the limited scope of these associations in our study points to a potential gap in the literature. Specifically, it raises questions about the extent and significance of brain structural changes in PACS. Although it was beyond the scope of our study, it's noteworthy that some researchers have investigated the utility of functional neuroimaging to deepen our understanding of PACS pathophysiology. Bungenberg et al., in a cross-sectional study, used resting-state functional MRI (fMRI) to examine participants with PACS. They discovered changes in several brain regionsincluding the brainstem, olfactory cortex, cingulate cortex, thalamus, and cerebellumon average seven months after SARS-CoV-2 infection. These alterations were associated with the severity of fatigue and cognitive functioning54. While structural MRI delineates the brain anatomy, fMRI sheds light on the brains dynamic functions. By revealing changes in brain activity and connectivity, fMRI could reveal underlying neural mechanisms of PACS that are not apparent in structural changes alone.
Our next approach in this study was to correlate clinical and neuroimaging features of this PACS cohort longitudinally. While a previous study has included both cognitive and neuroimaging assessment of PACS62, to our knowledge, this is the first study to include longitudinal analysis of both cognitive and neuroimaging tests. We found significant positive correlations between both global and focal measures of brain volume/thickness and visual memory scores, but not with other cognitive tests. This correlation indicated that worse visual memory was associated with lower total and subcortical GM volume together with left cerebral WM volume. Furthermore, subcortical GM volumes, especially the hippocampus and thalamus, significantly corresponded with worse visual memory performance. Previous studies also explored the association between GM volume and cognitive symptoms; it has been reported that worse memory and visuospatial test performance is associated with a loss of GM volume5,20. In line with previous studies, our longitudinal analyses revealed no evidence of volume gain in a 6-month period, nor did we find evidence of progressive volume loss broadly. However, we did observe significant gray matter loss in the left pallidum and left transverse cortical thickness. Despite these findings, we do not believe that they hold clinical significance. The observed changes in the left pallidum and left transverse cortical thickness were not associated with any clinical symptoms or functional impairments in our study population. Therefore, we do not interpret these findings as clinically meaningful54.
The majority of previous studies13,14,16,63,64,65,66, have reported high levels of plasma and/or CSF cytokines, NfL and GFAP in the acute or subacute phase of COVID-19 infection that normalize at follow-up, albeit using differing follow-up intervals64,67,68. Some of these studies related these biochemical changes with the severity of the infection or the gravity of neurological symptoms; however, there is no consensus on how fluid biomarkers relate to acute COVID-19 symptom severity, PASC symptoms, or PASC progression/resolution. In our study, the levels of plasma and CSF cytokines, NfL and GFAP were within pre-specified normal limits. Similar results were observed by Boesl et al.69, they found that NfL levels were normal in participants with self-reported cognitive complaints, and GFAP was altered in only 4%. They compared participants with subjective cognitive decline, single domain or multi-domain impairment and found no association between persistent neuronal or astrocytic damage and cognitive impairment. We observed slight differences in some cytokine levels between PACS and control participants, with variations of small magnitude. Furthermore, cytokine levels were either elevated or reduced compared to controls. Given the proximity of all values, even minimal differences in a subset of measurements could potentially lead to clinically significant results. Despite achieving statistical significance, we find this difficult to interpret and potentially inconclusive, and in our opinion, without clinical significance. However, it is worth mentioning that other studies in neurocognitive disorders show relationships between select cytokines with measures of cognitive function, and this warrants further examination. We did not observe significant differences in either GFAP or NfL levels between PACS participants relative to controls. Previous studies14,15,16,70,71 have inconsistent results regarding the association of fluid biomarkers with the severity of infection or neurological symptoms. This variability in findings from past studies may arise from methodological differences, diverse patient populations, and the dynamic nature of the post-acute phase of COVID-19. All the samples were negative for antineuronal antibodies. The absence of antineuronal antibodies in all samples holds clinical significance, suggesting that autoimmunity involving these specific antibodies may not be a predominant factor in the pathophysiology of PACS. This finding implies that cognitive impairment and neurological symptoms observed in PACS may be driven by mechanisms other than direct autoimmune responses targeting neurons.
We next sought to clarify whether these biochemical markers related to neuropsychological test results in PACS patients, as previous studies have inconsistent results regarding the association of inflammatory marker levels and neuropsychological tests. Results have ranged from no association72 to an association between cytokine levels and fatigue or executive functions (Stroop Color Word test)73, or TNF- levels and memory74. In our research, we discovered a surprising positive correlation between higher GFAP levels and enhanced Stroop Word test performance. Despite observing impairment in Stroop Word test results among participants, GFAP levels stayed within normal ranges, suggesting these levels might not substantially affect cognitive performance or act as a cognitive function marker. Contrary to the expected negative correlation between GFAP and cognitive testing, stemming from inflammation's assumed detrimental effects on cognition, our findings suggest otherwise. This could indicate a compensatory or specific role of glial cell activation in supporting cognitive functions, or potentially represent a Type I error. This intriguing result encourages further investigation to confirm these findings and uncover the mechanisms involved. No association was observed between cytokines, NfL, or GFAP levels and global or regional MRI measures after adjusting for multiple comparisons. Finally, we found that patients serum or CSF samples did not immunoreact with brain tissue or live neurons, suggesting that brain autoantibodies are not involved in PACS symptoms. While our study did not reveal any significant abnormalities in markers of neuronal damage, inflammation, or neuroimaging among individuals experiencing cognitive manifestations following COVID-19 infection, several potential pathophysiological mechanisms warrant consideration. It is plausible that subtle, yet to be identified systemic or central dysregulated immune responses or diffuse microvascular or barrier changes could contribute to cognitive manifestations. We might also consider the central role of fatigue in cognitive manifestations. Future research exploring these mechanisms in depth is crucial for a comprehensive understanding of the neurological sequelae of COVID-19 infection.
An interesting finding elucidated by this work is the breakdown of PACS amongst sex. Whereas COVID-19 infects women and men equally, related publications indicate that there is a higher prevalence of females with PACS, with percentages ranging from 63 to 74%13,16,75, in line with these observations, 79% of participants in this study were women. Interestingly, in a study including 377 patients with COVID-19 infection, the female sex was independently associated with PACS within the multivariable analysis75. The higher prevalence of PACS in females suggests multifaceted influences across biological, psychological, and social dimensions. Hormonal differences may affect immune responses and neuroinflammation, contributing to gender-based variations in susceptibility and outcomes. Psychologically, gender-specific stressors and coping mechanisms could impact symptom manifestation, requiring exploration of psychosocial aspects in the post-acute phase. Social disparities, including healthcare-seeking behavior and societal expectations, may further influence the identification and reporting of PACS symptoms. Acknowledging these complexities highlights the importance of customized research and treatment approaches for effectively addressing PACS in females.
A significant limitation of our study is the small sample size, which included only 49 participants at baseline and 46 at the 6-month follow-up visit. This limitation is particularly pronounced concerning CSF samples. The lumbar puncture procedure was designated as optional. Consequently, CSF samples were obtained from only 12 participants. As a result, the interpretation of our findings must be approached cautiously; a larger number of CSF samples would have provided a more robust basis for identifying differences compared to controls, if any. The statistical analyses have been adapted to the reduced data. Thus, it could be generalized our results. However, the unicentric nature of the study, even if limited in the sample size, also provided homogeneity to the data acquisition. Secondly, the present study neither has healthy participant controls nor participants with COVID-19 infection without cognitive complaints for neuropsychological or neuroimaging analyses. This was due to the review of the local Ethics Committee, which considered the inclusion of controls as too high of a demand. This study may face referral bias, as participants were referred by healthcare providers, potentially overrepresenting severe cases. Additionally, considering the heightened fear and anxiety surrounding COVID-19, some participants actively sought assistance and self-referred due to concerns about cognitive symptoms related to the virus. Further research should consider a more diverse and randomized sample to mitigate potential biases in interpreting the severity and prevalence of cognitive symptoms in PACS. Another limitation of the study lies in the absence of baseline cognitive assessments prior to COVID-19 infection, which could have offered valuable insights into pre- and post-infection cognitive changes. However, participants with previous cognitive impairment were excluded. Finally, we believe the current duration of this study was limited and that including a longer endpoint with greater distance between measurement intervals may be more suitable for studying PACS cognitive symptoms. However, the study was designed during the last quarter of 2020, even before the formal definition of PACS, and most studies then were designed with short follow-up periods20,64.
In conclusion, our study showed cognitive impairment, mainly affecting attention/executive and verbal memory functions lasting for at least 6months in individuals with PACS. Cognitive impairment was accompanied by depressive symptoms, apathy, anxiety, fatigue, and low health status. These findings (except for visual memory loss) were not associated with brain structural abnormalities, elevated cytokines, markers of neuronal damage, or neuronal antibodies. Given these findings, a tailored and multidisciplinary approach involving cognitive and mental health interventions is recommended for patient care. Future research is essential for understanding the enduring cognitive trajectory of PACS and the associated biological mechanisms. Longitudinal studies of extended duration will provide insights into the long-term cognitive impact. Addressing the gaps identified by our study's limitations, ongoing research endeavors are crucial to guide clinical interventions and enhance the overall management of PACS.
Participants
A non-probability cluster sampling strategy was used to recruit Flemish secondary school teachers. In August and September 2019, all secondary schools in Flanders (Belgium) were contacted through e-mail and telephone. To increase the response and participation rate, the Flemish Department of Education (Vlaams Departement Onderwijs) as well as all education networks (i.e., Flemish community schools, subsidised public schools, subsidised free schools) were involved in the recruitment and were asked to promote the study among all school principals. To stimulate school involvement, a convenient selection of schools in Flanders were visited to promote our study face-to-face. Schools that were willing to participate in the study were asked to send an e-mail with a link to an online questionnaire to their entire teaching staff. Furthermore, the same link was spread through social media (e.g., Facebook, Twitter) and by posting advertisements via the Flemish Department of Education. Teachers being in sick leave or having a distorted physical activity/dietary pattern (by e.g., injuries, diseases, following a diet) were excluded from the final sample. As this study was part of a larger longitudinal follow-up study, in which we questioned distorted physical activity/dietary patterns by one question, we could not differentiate between the two. As a result, participants who reported being distorted in either category were excluded.
This prospective cohort study is part of a larger longitudinal study, including six measurements throughout the 20192020 school year, i.e., Sep/Oct, Nov/Dec, Jan/Feb, Mar/Apr, May/Jun, and Jul/Aug. For the purpose of the present study (i.e., measuring the impact of COVID-19 lockdown on secondary school teachers PA and SB), the Jan/Feb measurement (Jan 27 Feb 11, 2020) will serve as baseline (T0). The measurement performed in Mar/Apr (Mar 23 Apr 7, 2020), which is five days after the installation of the lockdown measures, will serve as measurement under lockdown-exposure (i.e., primary endpoint (T1)). The measurements prior to T0 (i.e., Sep/Oct (T-2) and Nov/Dec (T-1)) will serve as pre control measurements, whereas the measurement after T1 (i.e., May/Jun (T2)) will serve as post control measurement. The Jul/Aug measurement was omitted due to anticipated summer holiday bias. The timeline of the measurements is displayed in Fig.1.
Timing of the measurements
At each time point participants were asked to complete an online questionnaire, including sample characteristics and primary outcome measures. Sample characteristics include socio-demographics, work-related information, and other health-related variables. Primary outcomes in the present study are PA and SB. During each measurement period of two weeks, three reminders were sent to the non-responders, each on the fourth, eighth and eleventh day after activation of the online questionnaire.
Socio-demographics include sex, age, highest diploma (i.e., secondary school degree, post-secondary school degree or certificate, Bachelors degree, Masters degree, PhD degree), having an extra job (yes/no), marital status (i.e., single, married, unmarried, living together with partner, divorced, widowed), having children (yes/no) and ethnicity (i.e., White European, White other, North-African, Afro-American, Indian, Middle-Eastern, South-Asian, Southeast-Asian, other). Work-related factors include education network (i.e., Flemish community schools, subsidised free schools, subsidised public schools) and total working hours per week. Health-related variables include self-reported height and weight (from which body mass index (BMI; kg/m) was calculated) and smoking status (yes/no).
The validated International Physical Activity Questionnaire (IPAQ Dutch long version) was used to estimate PA domains and intensities during the last seven days [23]. This self-report questionnaire includes 31 items and assesses four contextual PA domains: [1] work-related [2], transport-related [3], domestic and garden, and [4] leisure-time PA. The participants were asked to fill in the number of days and the amount of time (hours and minutes) spent in three different PA intensity levels within each domain, namely [1] walking [2], moderate-intensity PA, such as carrying light loads, washing windows, cycling or swimming at a regular pace, and [3] vigorous-intensity PA, such as heavy lifting, aerobics, running and fast cycling or fast swimming (as specified by the IPAQ). The outcome measures are domain- and intensity-specific PA as well as total PA expressed in min/week. Multiple criteria from the IPAQ scoring protocol were applied [24]: [1] only values of ten or more minutes of activity were retained; [2] non-relevant observations were excluded (e.g., answering in step counts instead of minutes); [3] PA levels higher than 960min/day (i.e., 16h/day) were excluded, as this would be unrealistic. Total scores per domain were calculated by multiplying the frequency of each PA per week by its duration expressed in minutes. Next, the domains were combined into total walking, moderate-intensity PA, and vigorous-intensity PA. Lastly, total PA was calculated by summing all items. It should be mentioned that total light-intensity PA, in which walking is just one component, is not questioned in the IPAQ. Therefore, total PA in this study only represents walking and moderate-to-vigorous-intensity PA. Note that the IPAQ scoring protocol includes a section Truncation of Data Rules, which is not applied in the current study. The protocol states that this rule attempts to normalize the distribution of levels of activity which are usually skewed in national or large population data sets [24]. Instead of truncating and forcing data into a normal distribution, we opted to tailor the statistical analyses to the non-normal data distributions (see Statistical analysis section). The IPAQ has fair to good psychometric properties (reliability: =0.80 and validity: r=0.30) [25].
SB was assessed by using the Dutch version of the validated context-specific sedentary behaviour questionnaire for adults developed by Busschaert and colleagues [26]. This self-report questionnaire assesses SB in three domains: [1] work-related [2], transport-related, and [3] leisure-time SB. Participants were asked to specify how much time they spent sitting/lying down during the last seven days (weekdays and weekend days separately) within each domain. The outcome measures are domain-specific SB as well as total SB expressed in min/week (i.e., sum score of minutes during the week and weekend). Participants were asked to fill in the number of days and the amount of time spent sitting/lying for several items/activities (e.g., TV watching, computer use, reading) within each of the three domains. For each item, a specific time interval could be chosen; e.g., 1 to 15min, 15 to 30min, 30 to 60min, 1 to 2h, etc. Midpoint values (e.g., 7.5min, 22.5min, 45min, 90min, etc.) of each test item interval were calculated. As it was not mentioned in the protocol how the upper limit time intervals more than seven hours a day and more than eight hours a day had to be interpreted, it was decided to consider these time intervals as 450min and 510min, respectively. Total sedentary time for an average day was estimated by summing all midpoint values of the specific SB contexts (weekdays and weekend days separately) and was estimated as follows: ((total sedentary time on a weekday * 5) + (total sedentary time on a weekend day * 2))/7. Although not explicitly mentioned in the paper of Busschaert and colleagues [26], but consistent with the IPAQ protocol, we decided to exclude participants with SB levels higher than 960min/day (i.e., 16h/day) from the analysis.
Patient and public involvement was not appropriate for this study.
Secondary school teachers from multiple geographical regions, urban and rural communities and different education networks were recruited for this study. Participants could report their sex, diploma and ethnicity. The author team included early, middle and late career researchers with balance from people who identify as male and female.
All data were analysed using R (R core Team, 2019; R Studio version 3.6.2) and SPSS (version 27). P-values<0.05 were considered statistically significant, whereas p-values between 0.05 and 0.10 were considered marginally significant. Representativeness of the sample at baseline (T0) was assessed by conducting two proportions z-tests. Drop-out analyses between baseline (T0) and the primary endpoint (T1) were conducted to assess possible selection bias of the retention group. In the first analysis, participants of whom we had data at T0 and T1 (i.e., retention group) were compared to participants of whom we only had data at T0 (i.e., drop-out group). As the generalized mixed models that we used typically include all available observation points, we decided to perform a second analysis in which we compared participants of whom we had data at T0 and T1 to participants of whom we only had data at T1. Independent samples t-tests, Mann-Whitney U tests and chi tests were conducted to detect possible differences between the drop-out group and retention group regarding total PA, total SB, sex, age, ethnicity, marital status, having children, smoking status, diploma, having an extra job, education network and BMI.
Multilevel models were used for data analysis. Preliminary analyses checked if a three level model was advised (repeated measures clustered within participants, participants clustered within schools) using graphical representations and by inspecting the amount of variance explained by each cluster. If necessary, one (or both) levels were dropped. Possible confounders, such as age and sex, were checked, but seemed to have no significant effects, and therefore no adjustments were made in the statistical models. The PA scale scores were non-normally distributed with continuous, positively skewed non-negative values. The SB scales also contained non-negative continuous values, but with less severe skewness. For both outcome variables, Gamma and Gaussian generalized linear mixed models were constructed using the R package lme4 [27]. To decide upon the model (i.e., Gamma or Gaussian) and link functions (i.e., log, inverse or identity), Bayesian Information Criterion (BIC) values were compared and a likelihood ratio test was performed (lrtest() function of the R package lmtest [28]). The model selection procedure of each outcome is explained in Additional file 1. For both PA and SB outcomes, the Gamma model with the log link function was selected. In total, five separate models (i.e., total PA, PA intensities, PA domains, total SB, SB domains) were analysed. In order to assess the effect of the lockdown on total PA and SB, a model with total PA and one with SB as outcome variable and time as predictor variable was fitted. To inspect the lockdown effect in the different domains (PA and SB) or intensities (PA), the same model was fitted but with the domains or intensities as a categorical predictor variable together with an interaction term between time and domains or intensities. Significance of main and interaction effects of the categorical variables consisting of more than two categories were checked using Wald Chi tests (Anova function from the R package car [29]). Contrasts were constructed (test Interactions function from the R package phia [30]) to inspect statistical differences between T0 and T-2, T-1, T1, T2 of each domain and intensity, respectively. Data visualisation was performed using the R packages ggplot2 [31] and sjPlot [32], based on the predicted values of the response variable. More detailed information on the statistical analysis procedure can be found in Additional file 2.
