Tag: SARS-CoV-2

  • Study reveals early death predictors in COVID-19 patients with cardiac injury

    Study reveals early death predictors in COVID-19 patients with cardiac injury

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    Announcing a new article publication for Cardiovascular Innovations and Applications journal. The activation of immune and thrombotic biomarkers at admission, and their ability to predict cardiac injury and mortality patterns in COVID-19, remains unclear.

    This retrospective cohort study included 170 patients with COVID-19 with cardiac injury at the time of admission to Tongji Hospital in Wuhan between January 29, 2020, and March 8, 2020. The temporal evolution of inflammatory cytokines, coagulation markers, clinical treatment, and mortality were analyzed. Continuous variables are expressed as median (interquartile range). The Mann-Whitney test was used for two-group comparisons, whereas the Kruskal-Wallis test was used for comparisons among three groups. Categorical variables are expressed as proportions and percentages, and Fisher’s exact test was used to compare differences. A multivariate regression model was used to predict in-hospital death. A simple linear regression analysis was applied to examine the correlation between baseline biomarkers and peak cTnI levels.

    Of the 170 patients, 60 (35.3%) died early (<21 d), and 61 (35.9%) died after a prolonged stay. The admission laboratory findings correlating with early death were elevated interleukin 6 (IL-6) (P < 0.0001), tumor necrosis factor-α (P = 0.0025), and C-reactive protein (P < 0.0001). We observed the trajectory of biomarker changes in patients after admission hospitalization, and determined that early mortality was associated with a rapidly increasing D-dimer level, and gradually decreasing platelet and lymphocyte counts. Multivariate and simple linear regression models indicated that the risk of death was associated with immune and thrombotic pathway activation. Elevated admission cTnI levels were associated with elevated IL-6 (P = 0.03) and D-dimer (P = 0.0021) levels.

    In patients with COVID-19 with cardiac injury, IL-6 and D-dimer levels at admission predicted subsequently elevated cTnI levels and early death, thus highlighting the need for early inflammatory cytokine-based risk stratification in patients with cardiac injury.

     

    Source:

    Journal reference:

    Peng, K., et al. (2024). IL-6 and D-dimer Levels at Admission Predict Cardiac Injury and Early Mortality during SARS-CoV-2 Infection. Cardiovascular Innovations and Applications. doi.org/10.15212/cvia.2024.0009.

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  • Study reveals how long COVID can affect brain function through vascular disruption

    Study reveals how long COVID can affect brain function through vascular disruption

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    In a recent study published in Nature Neuroscience, researchers investigated whether the neurological response to coronavirus disease 2019 (COVID-19) may be due to brain-brain barrier (BBB) disruption and subsequent extravasation of serum components.

    Study: Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Image Credit: fran_kie/Shutterstock.comStudy: Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Image Credit: fran_kie/Shutterstock.com

    Background

    COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a respiratory viral infection resulting in severe acute respiratory distress syndrome (ARDS) and long-term neurological consequences such as headache, lethargy, malaise, and altered consciousness.

    BBB breakdown allows serum components and cytokines to penetrate the brain. The cerebrovascular pathophysiology and processes remain unknown, warranting further research.

    About the study

    The present study determined the association between COVID-19-related cognitive impairment and BBB breakdown in COVID-19 patients.

    The researchers collected blood and plasma samples from 76 acute COVID-19 patients, evaluated them for inflammatory, coagulation, and BBB dysfunction indicators, and rated their severity using World Health Organization (WHO) severity guidelines.

    They next examined brain fog status to identify changes in patients’ inflammatory profiles. During the first round of COVID-19 in March and April 2020, they recruited participants from St. James’ Hospital at Trinity College in Dublin.
    To investigate BBB function, the researchers selected ten recovered individuals, 11 suffering from long COVID or post-acute COVID-19 (PASC) and 11 with PASC-related brain fog, diagnosed with SARS-CoV-2 infection during the disease’s April 2020 outbreak in Ireland.

    All patients had polymerase chain reaction (PCR)-verified moderate-intensity COVID-19, requiring no antiviral therapy or hospitalization.

    The researchers used the quick smell identification test (Q-SIT) to evaluate anosmia status, grouping them based on self-reported cognition difficulties known as brain fog.

    They classified subjects as recovered in the case of no symptom recurrence after recovering from acute COVID-19. They used the Montreal Cognitive Assessment (MOCA) to measure cognitive impairment.

    The researchers used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) volume and thickness measurements on recovered individuals with PASC and 60 age-matched healthy controls from the IXI dataset to investigate structural brain alterations associated with increased BBB permeability.

    They used multiplexed assays to assess 50 BBB integrity and inflammation markers and correlation analysis adjusting for age and sex to identify associations between neuroinflammatory and BBB dysfunction markers in the recovered and PASC cohort.

    RNA-seq was also used to evaluate gene expression alterations in peripheral blood mononuclear cells (PBMCs) and the human brain endothelial cell line hCMEC/d3 isolated from unaffected, recovered, and patients with protracted COVID in the absence or presence of brain fog.

    They used gene ontology (GO) to examine the transcriptome profiles of those with and without brain fog in the group with extended COVID.

    The study included COVID-19 convalescents aged ≥18 years without neurological symptoms and individuals suffering from long-term COVID with symptoms lasting over 12 weeks after infection.

    Results

    COVID-19-induced brain fog was associated with BBB impairment. This disturbance is visible during acute COVID-19 and in individuals with long-term COVID-related cognitive impairment, popularly termed brain fog.

    In addition, the team found that PBMCs showed coagulation system instability and a suppressed adaptive immunological response in those with brain fogging.

    In vitro, PBMCs showed enhanced adherence to cells of the human brain endothelium, whereas the endothelial cells were exposed to sera from individuals with prolonged COVID-19-induced inflammation.

    The findings indicated that assessing BBB integrity might be a clinically helpful indicator of neurological sequelae linked with COVID-19 in a few individuals. Furthermore, targeted control of BBB integrity may provide a novel strategy for therapeutically treating patients with chronic COVID.

    Common symptoms of brain fog include dyspnea, loss of smell and taste, coughing, weariness, and fever. Patients with brain fogging had a higher average age, were more likely to be hospitalized, and needed oxygen treatment.

    There was a strong association between COVID-19 severity and age, hospitalization length, and comorbidities.

    BBB failure was linked to long-term COVID-induced cognitive impairment, indicating that both active and acute SARS-CoV-2 infections may cause BBB dysfunction in individuals with neurological disabilities.

    MRI imaging indicated significantly higher brain leakage in individuals with PASC and brain fog, with volumetric deficits mostly in the frontal and temporal lobes and increases in the occipital lobes and lateral ventricles.

    White blood cells from COVID-19 patients stimulated brain endothelial cells. Compared to unaffected individuals, there were 950 differentially expressed genes (DEGs) in recovered individuals, 481 in individuals with protracted COVID, and 126 in those with brain fogging.

    Upregulated genes were associated with T cell development and activation pathways, immune response negative control, and gene expression circadian regulation.

    Conclusion

    Overall, the study findings showed that PASC-related brain fog is associated with systemic inflammation and persistent localized BBB malfunction, with disruption apparent up to a year after infection.

    Dysregulation of the coagulation system is a primary cause of prolonged COVID-19. BBB disruption is associated with neurological impairment during acute COVID-19, and high serum levels in neurological diseases such as epilepsy, traumatic brain injury, and schizophrenia.

    Understanding the long-term effects of COVID-19 is critical to developing new treatments.

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  • SARS-CoV-2-infection and vaccine-induced antibodies wane initially but stabilize for lasting protection

    SARS-CoV-2-infection and vaccine-induced antibodies wane initially but stabilize for lasting protection

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    In a recent observational study published in the journal Immunity, researchers from the United States of America investigated the longevity of antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination. They found that the humoral responses to SARS-CoV-2 infection and vaccination were long-lasting and biphasic, with an initial decline followed by stabilization after seven to nine months.

    Study: SARS-CoV-2-infection- and vaccine-induced antibody responses are long lasting with an initial waning phase followed by a stabilization phase. Kateryna Kon / ShutterstockStudy: SARS-CoV-2-infection- and vaccine-induced antibody responses are long lasting with an initial waning phase followed by a stabilization phase. Kateryna Kon / Shutterstock

    Background

    The COVID-19 pandemic, which began four years ago, prompted the rapid development of messenger RNA (mRNA) vaccines, including the BNT162b2 and mRNA-1273, helping save millions of lives. However, emerging variants of SARS-CoV-2 and the waning immunity against them pose challenges. Although mRNA-based vaccine-induced immunity is perceived to decline rapidly, this perception is based on limited data, primarily from short-term studies.

    Amidst the exponential rise of SARS-CoV-2 cases in March 2020, the New York metropolitan area faced a crisis, with essential healthcare workers at a high infection risk. In response, a specific and sensitive SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) was developed, and the Protection Associated with Rapid Immunity to SARS-CoV-2 (PARIS) study was launched. This initiative tracked antibody responses, reinfection rates, and immunity factors in healthcare workers, offering vital insights into pandemic dynamics. Researchers in the present study utilized data from the PARIS study, one of the most comprehensive investigations on SARS-CoV-2 immunity longevity, and analyzed the humoral responses to SARS-CoV-2 infection and vaccination.

    About the study

    The PARIS study was an observational, longitudinal study conducted from April 2020 to March 2023 and enrolled 501 healthcare workers. Their mean age was 41 years, and 67% of them were female. Weekly saliva samples and bi-weekly blood samples were collected for the first two months. Nasopharyngeal/ante-near swabs were taken for respiratory symptoms or after vaccination. About 38% of participants showed baseline SARS-CoV-2-spike-binding immunoglobulin G (IgG) antibodies. A total of 93% of participants were vaccinated– 0.2% received four mRNA boosters, 2.6% had three boosters, 16.6% had two boosters, and 53.7% had one booster. Approximately 21.3% of the participants chose not to receive boosters.

    The study utilized REDCap for monthly surveys on general health and SARS-CoV-2 risk, focusing on side effects after mRNA vaccinations and booster doses. Data from 228 participants were analyzed, and severity scoring was conducted, revealing reported incidence and severity trends across doses and subgroups.

    Antibody titers in serum were assessed using enzyme-linked immunosorbent assay (ELISA) and optical density at 490 nm (OD490). Statistical and quantitative analysis involved the use of the Wilcoxon test, Mann-Whitney U test, log-rank test, unweighted pair group method with arithmetic mean (UPGMA) clustering, antibody kinetic modeling including nonlinear mixed-effects (NLME) models, and demographic factor assessment in post-vaccine and post-boost models.

    Results and discussion

    While 38% of the participants had detectable spike-binding IgG antibodies at baseline, 62% were seronegative at the first visit. Vaccination-naïve individuals exhibited low antibody titers after the first mRNA vaccine dose, with a substantial increase after the second dose. However, individuals with pre-existing immunity reached higher and faster peak titers, maintaining over threefold higher responses after primary immunization.

    Seven to nine months post-primary vaccination, antibody titers were found to achieve a steady state. Individuals with hybrid immunity maintained higher and more stable titers compared to naïve recipients, indicating the induction of long-lasting serum antibodies. Furthermore, vaccine type and age were found to affect the antibody titers in participants without hybrid immunity modestly. As per the study, the administration of booster doses elevated the threshold at which long-term serum antibody responses reached a stable state.

    A total of 225 SARS-CoV-2 infections were observed in the study period, predominantly occurring after immunization, with breakthrough infections more prevalent during the Omicron wave. In individuals with vaccine-only immunity, breakthrough infections acted as equivalent boosts to antibody responses, while in those with hybrid immunity, vaccination had a more robust boosting effect compared to a second infection.

    Participants with pre-existing immunity experienced more side effects after the first vaccine dose, with overall reactogenicity decreasing after subsequent doses. Booster doses induced fewer systemic side effects than the second dose in naïve participants, while those with hybrid immunity had a different pattern, showing slightly increased side effects with booster doses.

    However, the study is limited by the inability to analyze mucosal immune responses, the lack of measuring neutralizing antibodies or antibodies to specific epitopes, and the lack of assessment of later variant spikes or nucleoprotein.

    Conclusion

    In conclusion, the present study provides evidence that antibody responses to SARS-CoV-2 mRNA vaccination exhibit a classical biphasic decay, transitioning from rapid waning to stabilization. The findings emphasize the prolonged protection provided by hybrid immunity against several variants and the potential booster-like effect of breakthrough infections in enhancing immunity.

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  • Identifying antiviral protein IFN-γ as a potential biomarker for Long COVID

    Identifying antiviral protein IFN-γ as a potential biomarker for Long COVID

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    SARS-CoV-2 triggers the production of the antiviral protein IFN-γ, which is associated with fatigue, muscle ache and depression. New research shows that in Long COVID patients, IFN-y production persists until symptoms improve, highlighting a potential biomarker and a target for therapies.

    Identifying antiviral protein IFN-γ as a potential biomarker for Long COVID
    Woman sitting on sofa in the dark, placing a hand to her forehead. Image Credit: Annie Spratt via Unsplash

     A University of Cambridge-led study identifies the protein interferon gamma (IFN-γ) as a potential biomarker for Long COVID fatigue and highlights an immunological mechanism underlying the disease, which could pave the way for the development of much needed therapies, and provide a head start in the event of a future coronavirus pandemic.

     The study, published today in Science Advances, followed a group of patients with Long COVID fatigue for over 2.5 years, to understand why some recovered and others did not.

    Long COVID continues to affect millions of people globally and is placing a major burden on health services. An estimated 1.9 million people in the UK alone (2.9% of the population) were experiencing self-reported Long COVID as of March 2023, according to the ONS. Fatigue remains by far the most common and debilitating symptom and patients are still waiting for an effective treatment.

    The study shows that initial infection with SARS-CoV-2 triggers production of the antiviral protein IFN-γ, which is a normal reaction from the immune system. For most people, when their infection clears, COVID-19 symptoms cease and production of this protein stops, but the researchers found that high levels of IFN-γ persisted in some Long COVID patients for up to 31 months.

    We have found a potential mechanism underlying Long COVID which could represent a biomarker – that is, a tell-tale signature of the condition. We hope that this could help to pave the way to develop therapies and give some patients a firm diagnosis.

    Dr Benjamin Krishna, Co-author, Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID).

    The research began in 2020 when Dr Nyarie Sithole set up a Long COVID clinic in Cambridge’s Addenbrooke’s Hospital, where he started collecting blood samples from patients and set about studying their immunology. Sithole soon enlisted the support of Dr Benjamin Krishna and Dr Mark Wills from the University of Cambridge’s Dept. of Medicine.

    “When the clinic started, a lot of people didn’t even believe Long COVID was real,” Dr Sithole said. “We are indebted to all the patients who volunteered for this study, without whose support and participation we would obviously not have accomplished this study.”

    The team studied 111 COVID-confirmed patients admitted to Addenbrooke’s Hospital CUH, Royal Papworth Hospital and Cambridge and Peterborough NHS Foundation Trusts at 28 days, 90 days and 180 days following symptom onset. Between August 2020 and July 2021, they recruited 55 Long COVID patients – all experiencing severe symptoms at least 5 months after acute COVID-19 – attending the Long COVID clinic at Addenbrooke’s.

    The researchers analysed blood samples for signs of cytokines, small proteins crucial to the functioning of immune system cells and blood cells. They found that the white blood cells of individuals infected with SARS-CoV-2 produced IFN-γ, a pro inflammatory molecule, and that this persisted in Long COVID patients.

    Dr Krishna said: “Interferon gamma can be used to treat viral infections such as hepatitis C but it causes symptoms including fatigue, fever, headache, aching muscles and depression. These symptoms are all too familiar to Long COVID patients. For us, that was another smoking gun.”

    By conducting ‘cell depletion assays’, the team managed to identify the precise cell types responsible for producing IFN-γ. They pinpointed immune cells known as CD8+ T cells but found that they required contact with another immune cell type: CD14+ monocytes.

    Previous studies have identified IFN-γ signatures using different approaches and cohorts, but this study’s focus on fatigue revealed a much stronger influence. Also, while previous studies have noticed IFN-y levels rising, they have not followed patients long enough to observe when they might drop back down.

    The Cambridge team followed its Long COVID cohort for up to 31 months post-infection. During this follow up period, over 60% of patients experienced resolution of some, if not all, of their symptoms which coincided with a drop in IFN- γ.

    Vaccination helping Long COVID patients

    The team measured IFN-γ release in Long COVID patients before and after vaccination and found a significant decrease in IFN-γ post vaccination in patients whose symptoms resolved.

    If SARS-CoV-2 continues to persist in people with Long COVID, triggering an IFN-γ response, then vaccination may be helping to clear this. But we still need to find effective therapies,” Dr Krishna said.

    The number of people with Long COVID is gradually falling, and vaccination seems to be playing a significant role in that. But new cases are still cropping up, and then there is the big question of what happens when the next coronavirus pandemic comes along. We could face another wave of Long COVID. Understanding what causes Long COVID now could give us a crucial head start.

    Microclotting

    Some well-publicised previous studies have proposed microclotting as a principle cause of Long COVID.

    While not ruling out a role of some kind, these new findings suggest that microclotting cannot be the only or the most significant cause.

    Classifying long COVID

    This study argues that the presence of IFN-γ could be used to classify Long COVID into subtypes which could be used to personalise treatment.

    It’s unlikely that all the different Long COVID symptoms are caused by the same thing. We need to differentiate between people and tailor treatments. Some patients are slowly recovering and there are those who are stuck in a cycle of fatigue for years on end. We need to know why,” Dr Krishna said.

    Source:

    Journal reference:

    Krishna, B. A., et al. (2024) Spontaneous, persistent, T cell–dependent IFN-γ release in patients who progress to Long Covid. Science Advances. doi.org/10.1126/sciadv.adi9379.

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  • Save lives in the next pandemic: ensure vaccine equity now

    Save lives in the next pandemic: ensure vaccine equity now

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    Since 2022, member states of the World Health Organization (WHO) have been negotiating a new treaty — provisionally termed the Pandemic Agreement. If adopted, it would transform how the world handles pandemic prevention, preparedness and response. Opinions differ on what negotiators should prioritize. But no issue has captivated public attention as much as vaccine equity — or done more to bring countries to the negotiating table.

    During the COVID-19 pandemic, scientists began to design vaccine candidates only a few hours after the first SARS-CoV-2 genome sequence was shared. By the end of 2020, mass vaccination had begun in the United States and Europe. High-income countries promised to share vaccines through the voluntary WHO COVID-19 Vaccines Global Access (COVAX) programme, but failed to meet their commitments. When South Africa and India appealed to the World Trade Organization for an emergency waiver of intellectual-property rights related to COVID-19 vaccines, so that every country could start their own manufacturing, high-income countries blocked the proposal for months. The refusal of wealthier nations to cooperate had cost between 200,000 and 1.3 million lives by the end of 2021 in low- and middle-income countries1,2. Today, nearly one-third of the world’s population has still not received a single dose, and the death toll resulting from vaccine nationalism continues to grow.

    The Pandemic Agreement could be the last chance to fix this problem before the next COVID-19 arrives. Yet the proposed solution — the Pathogen Access and Benefit-Sharing (PABS) System, which was outlined in Article 12 of the latest treaty draft — still hangs in the balance. The second-to-last session of the treaty’s Intergovernmental Negotiating Body is now under way. So far, countries have been unable to agree on this part of the text. As time runs out, we urge WHO member states to agree on a ‘science-for-science’ mechanism that ensures vaccine equity in the next pandemic.

    The road to PABS

    Across all fields, scientists from the global north have frequently extracted data and samples from the global south without the permission of the people there, without collaborating meaningfully — if at all — with local scientists, and without providing any benefit to the countries where they conduct their work. In 1993, the Convention on Biological Diversity recognized parties’ sovereign rights to their ‘genetic resources’. Since 2014, under the Nagoya Protocol on Access and Benefit-sharing, countries have developed their own legislation to ensure that they receive benefits (such as financial compensation or scientific collaboration) when scientists and others from outside the country access their genetic resources.

    Discussions on access and benefit-sharing in global health began in earnest in 2007, when the Indonesian government refused to share avian influenza samples with the rest of the world, on the grounds that such samples were often used to make vaccines that were never made available in most places3. Sparked by this conflict — and the 2009 H1N1 flu pandemic — WHO member states developed the 2011 Pandemic Influenza Preparedness (PIP) Framework to streamline the sharing of influenza viruses with pandemic potential, as well as vaccines and other benefits.

    A doctor places a stethoscope on a patient's back in a hospital

    After the 2009 H1N1 influenza pandemic, the World Health Organization designed a plan for global sharing of flu viruses and vaccines. The same must be done for all viruses with pandemic potential.Credit: James Hill/Redux/eyevine

    Under the PIP Framework, 14 manufacturers have promised that when the next influenza pandemic starts, they will share up to 10% of the vaccines that they make (around 420 million doses) with the WHO. In exchange, these companies have access to a global network of laboratories and their flu samples. The PIP model shows significant promise, but is so far untested and applies only to influenza.

    The proposed PABS System in the Pandemic Agreement would take lessons from the PIP Framework and apply an access and benefit-sharing scheme to any pathogen with pandemic potential, such as SARS-CoV-2. Under the PABS System, scientists would share pathogen samples and data through a global network of laboratories and sequence data repositories. In exchange for access to samples and data, manufacturers of vaccines or therapeutics would give at least 20% of their products to the WHO (half for free, and half at affordable prices). The WHO would then distribute these on the basis of public-health risk and needs. Users of the PABS System would also contribute to a capacity-development fund, and be encouraged to explore other kinds of benefit-sharing, such as scientific collaborations and technology transfer.

    Science-for-science

    With regard to physical samples, the Nagoya Protocol and its national implementing legislation can be cumbersome to navigate4. Some scientists are apprehensive about the idea of introducing similar barriers into work with genetic sequence data, especially during outbreaks.

    In relation to the Nagoya Protocol, several professional societies, including the American Society for Microbiology, have endorsed a group of US scientists that opposes “any restriction or control of access and/or use” of any genetic sequences (see go.nature.com/3i5ds). Comments from sessions indicate that such concerns are increasingly being echoed by representatives of global north countries in the current Pandemic Agreement negotiations. Some critics have even argued that the proposals for PABS would block progress towards open science, in favour of a transactional approach5.

    As a collective of 290 scientists from 36 countries, we argue that a pandemic treaty cannot succeed unless it ensures that everyone will benefit from pandemic science.

    Under the new treaty, should it be adopted with the current vision of the PABS System, countries will still be expected to ensure that their scientists share lifesaving data openly and rapidly. Scientists will still be able to share their data freely outside of PABS platforms, and widely used databases could enter into the PABS System — meaning that most researchers would never experience any disruptions to their workflow. The WHO could also establish its own repository or clearinghouse for genetic sequence data and samples, which would potentially provide scientists with more transparent management of these resources and the guarantee of continued access.

    Financing committed largely by pharmaceutical firms using these platforms (which sometimes directly derive profits from publicly funded science) would, in turn, go towards expanding sequencing capacity and scientific research in low-resource settings. It would also help to support other priorities, such as pandemic prevention6. What’s more, scientists everywhere, but especially in the global south, would benefit from a system that creates opportunities for international collaboration — and that ensures that people receive credit for sharing their data.

    Hold the course

    Access and benefit-sharing could just as easily be called ‘science for science’: the PABS System will support more pandemic science, and ensure that scientists’ contributions result in their communities having access to lifesaving advancements.

    Earlier this week, the Intergovernmental Negotiating Body for the Pandemic Agreement reconvened for its penultimate session. If Article 12 is weakened or dismantled, it will be a monumental setback for global health justice — and for the global scientific community.

    Although today’s scientific community has embraced the ideals of open data sharing, the world is no closer to a fair system for sharing vaccines and therapeutics. Intellectual property, not benefit-sharing, is the antithesis of open science. We dream of a world in which such barriers are dismantled for lifesaving medicines. Until that day, the Pandemic Agreement offers the last best chance to avoid repeating the mistakes made during the COVID-19 pandemic.

    Competing Interests

    C.C. has previously received funding support from the Coalition for Epidemic Preparedness Innovations, and has been a consultant for the US Department of State on Global Health issues. D.B. is a member of the Lancet-PPATS Commission on Prevention of Viral Spillover. A.P. has advised multiple countries pro bono on the treaty negotiations and has consulted for the WHO on international law. C.C. and A.P. receive funding support from the Carnegie Corporation of New York and the US National Science Foundation for research related to the Pandemic Agreement. We declare no other competing interests.

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  • Study reveals high prevalence of persistent COVID-19 infections in general population

    Study reveals high prevalence of persistent COVID-19 infections in general population

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    A new study led by the University of Oxford has found that a high proportion of SARS-CoV-2 infections in the general population lead to persistent infections lasting a month or more. The findings have been published today in the journal Nature.

    It has long been thought that prolonged COVID-19 infections in immunocompromised individuals may have been the source of the multiple new variants that arose during the coronavirus pandemic and seeded successive waves of infection, including the Alpha and Omicron variants. But until now, the prevalence of persistent COVID-19 infections in the general population and how the virus evolves in these situations remained unknown.

    To investigate this, the researchers used data from the Office for National Statistics Covid Infection Survey (ONS-CIS), which tested participants approximately monthly. Of the 90,000+ participants, 3,603 provided two or more positive samples between November 2020 to August 2022 where the virus was sequenced. Of these, 381 individuals tested positive with the same viral infection over a period of a month or longer. Within this group, 54 individuals had a persistent infection which lasted at least two months. The researchers estimate that between one in a thousand to one in 200 (0.1-0.5%) of all infections may become persistent, and last for at least 60 days.

    In some cases, individuals remained infected with viral variants that had gone extinct in the general population. In contrast, the researchers found that reinfection with the same variant was very rare, likely due to the host developing immunity to that variant and the variant reducing in frequency to very low levels after a few months.

    Of the 381 persistent infections, 65 had three or more PCR tests taken over the course of their infection. Most (82%) of these individuals demonstrated rebounding viral dynamics, experiencing high, then low, then high viral load dynamics. According to the researchers, this demonstrates that the virus can maintain the ability to actively replicate during prolonged infections.

    In the study, people with persistent infections were 55% more likely to report having Long-COVID symptoms more than 12 weeks since the start of the infection than people with more typical infections.

    Certain individuals showed an extremely high number of mutations, including mutations that define new coronavirus variants, alter target sites for monoclonal antibodies, and introduce changes to the coronavirus spike protein. However, most individuals did not harbour a large number of mutations, suggesting that not every persistent infection will be a potential source for new concerning variants.

    Our observations highlight the continuing importance of community based genomic surveillance both to monitor the emergence and spread of new variants, but also to gain a fundamental understanding of the natural history and evolution of novel pathogens and their clinical implications for patients.”


    Dr Mahan Ghafari, Co-lead author of the study, Pandemic Sciences Institute, Nuffield Department of Medicine, University of Oxford

    Co-lead author Dr Katrina Lythgoe (Department of Biology and Pandemic Sciences Institute, University of Oxford) said: ‘Although the link between viral persistence and Long Covid may not be causal, these results suggest persistent infections could be contributing to the pathophysiology of Long Covid. Indeed, many other possible mechanisms have been suggested to contribute to Long Covid including inflammation, organ damage, and microthrombosis.’

    Source:

    Journal reference:

    Ghafari, M., et al. (2024). Prevalence of persistent SARS-CoV-2 in a large community surveillance study. Nature. doi.org/10.1038/s41586-024-07029-4.

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  • Survey of US adults reveals common cognitive symptoms in post-COVID-19 patients, linked to impaired daily functioning and depression

    Survey of US adults reveals common cognitive symptoms in post-COVID-19 patients, linked to impaired daily functioning and depression

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    In a recent study published in the journal JAMA Network Open, a team of scientists examined how prevalent self-reported cognitive symptoms were in individuals with post-coronavirus disease 2019 (COVID-19) condition as compared to individuals who had prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections but had not developed post-COVID-19 condition. They also evaluated the impact of these cognitive symptoms on mood, function, and employment status.

    Study: Cognitive Symptoms of Post–COVID-19 Condition and Daily Functioning. Image Credit: PeopleImages.com - Yuri A/Shutterstock.com
    Study: Cognitive Symptoms of Post–COVID-19 Condition and Daily Functioning. Image Credit: PeopleImages.com – Yuri A/Shutterstock.com

    Background

    One of the long-term impacts of the COVID-19 pandemic has been post-COVID-19 condition, commonly referred to as long coronavirus disease (long COVID), where the symptoms of acute SARS-CoV-2 infections persist or remerge months after recovering from the initial infection. The condition consists of wide-ranging symptoms affecting numerous organ systems, with fatigue, shortness of breath, and post-exertional malaise being the most common symptoms.

    Changes in mood and cognitive impairments have also been reported, with studies confirming the long-lasting impact of SARS-CoV-2 infections on neurological health. These persistent physical and neurological symptoms continue to have a significant impact on the functioning and quality of life of the patients long after they have recovered from the initial infection. Understanding how this condition impacts the individual’s productivity or employment status is essential to forming effective treatment mechanisms and public health strategies.

    About the study

    In the present study, the researchers used data from a survey conducted across the United States (U.S.) during two COVID-19 waves among individuals who had reported post-COVID-19 condition symptoms and those who reported complete recovery after a SARS-CoV-2 infection. The data was collected between December 2022 and January 2023 and then again from April to May 2023 across 50 U.S. states.

    The participants were above 18 years of age, and the study population was balanced for demographic factors such as gender, age, race, and ethnicity. A validated measure for patient-reported outcomes was used to design the questions on cognitive symptoms, which largely included questions on how often patients experienced specific symptoms over the previous week with replies on a five-point scale.

    The questions addressed the prevalence of symptoms such as trouble remembering, trouble starting tasks, slowed thinking, finding multitasking difficult, decision-making problems, and needing to pay extra attention to avoid errors. The number of symptoms and presence of these symptoms based on an occurrence rate of at least once a day were recorded for each patient.

    A nine-item questionnaire was also used to assess depressive symptoms in patients. Additionally, the patients were asked to describe how these cognitive post-COVID-19 symptoms interfered with their daily activities. The employment status of the participants was also recorded and categorized as full-time, contract, part-time, self-employed, homemaker, student, retired, or unemployed.

    Sociodemographic information collected from the participants included self-reported race and ethnicity data. The initial SARS-CoV-2 infection and post-COVID-19 condition were defined based on self-reported symptoms from the participants, such as reports of positive test results for COVID-19.

    Results

    The results showed that cognitive symptoms were prevalent in individuals experiencing post-COVID-19 conditions, and these symptoms were associated with functional impairments and a lower likelihood of holding full-time employment. The severity of depressive symptoms was also greater for individuals with cognitive post-COVID-19 symptoms.

    The number of individuals with post-COVID-19 condition who reported experiencing cognitive impairments was significantly higher than those who reported cognitive symptoms but did not have post-COVID-19 condition. Furthermore, women, younger individuals, and people with lower income levels showed a higher prevalence of cognitive symptoms than those in other sociodemographic groups.

    The researchers believe that the higher prevalence of cognitive impairments reported among younger individuals could be due to the notable change from the baseline measurements before the COVID-19 pandemic. Among older individuals, who might already be experiencing cognitive decline associated with age, the cognitive impairments due to post-COVID-19 condition might not be as apparent as in younger individuals.

    The study also suggested that the association between increased prevalence of cognitive impairments among individuals from lower-income households could reflect the influence of economic stress on the vulnerability to cognitive symptoms of post-COVID-19 conditions.

    Conclusions

    Overall, the study found that cognitive decline was highly prevalent among individuals with long COVID or post-COVID-19 conditions, especially among younger individuals, women, and those from low-income households.

    Furthermore, the probability of full-time employment was found to be lower among individuals experiencing cognitive impairments due to long COVID, highlighting the need for public health strategies and treatment measures to improve the quality of life and functional abilities of individuals suffering from post-COVID-19 condition.

    Journal reference:

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  • Study reveals seasonal MERS-CoV peaks in Kenyan camels and potential human transmission

    Study reveals seasonal MERS-CoV peaks in Kenyan camels and potential human transmission

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    In a recent study published in the CDC’s journal Emerging Infectious Diseases, researchers estimated the incidence and potential human transmission of the Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedaries (nomadic camels) in northern Kenya. They found that the incidence of MERS-CoV among these animals was biphasic, peaking in October 2022 and February 2023. Further, slaughterhouse workers in contact with the dromedaries were found to show serologic signs of exposure to MERS-CoV.

    Dispatch: Biphasic MERS-CoV Incidence in Nomadic Dromedaries with Putative Transmission to Humans, Kenya, 2022–2023. Image Credit: Hamady / ShutterstockDispatch: Biphasic MERS-CoV Incidence in Nomadic Dromedaries with Putative Transmission to Humans, Kenya, 2022–2023. Image Credit: Hamady / Shutterstock

    Background

    MERS-CoV is prevalent in dromedary camels in the Arabian Peninsula and Africa, with >75% seroprevalence. Zoonotic transmission to humans, mainly in the Arabian Peninsula, has resulted in >2,400 cases and >800 deaths so far. Although camel breeding is a major activity in Kenya, only three cases of MERS-CoV were identified in camel-exposed humans in 2019, suggesting regional epidemiologic differences.

    MERS-CoV outbreaks in farmed dromedary camels are linked with annual camel parturition, with calves testing positive for MERS-CoV ribonucleic acid (RNA) after losing maternal antibodies. Nomadic camels in Africa, with fluctuating population densities due to seasonality and food availability, have shown correlations between high population density and MERS-CoV seropositivity in Kenya, indicating gaps in our understanding of MERS-CoV circulation.

    Limited infrastructure hinders field studies on nomadic camels, but the regular transportation of these animals to slaughterhouses allows for continuous testing. Leveraging this setup, researchers in the present study conducted a year-long study at a northern Kenyan slaughterhouse hub to estimate the MERS-CoV incidence in dromedaries and their potential transmission to individuals working there.

    About the study

    The study was conducted at a slaughterhouse hub in Isiolo, northern Kenya. Sampling was conducted from September 2022 to September 2023. Samples were collected from 10-15 dromedary camels at a frequency of 4-5 days per week. The camels (n = 2,711) originated from various administrative wards (n=12), primarily from Laisamis and Burat.

    MERS-CoV RNA detection was performed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Confirmation was done by open reading frame (ORF) 1ab qRT-PCR or sequencing. Phylogenetic analysis was additionally performed. Randomized camel serum samples (n = 369) were tested to assess MERS-CoV immunoglobulin G (IgG) levels using ELISA (short for enzyme-linked immunosorbent assay). Optical density ratio (ODR) values were obtained. Statistical analyses were conducted to explore the associations between MERS-CoV IgG levels, RNA-positivity, seasonality, camel sex, and age.

    Sero-epidemiologic investigation was conducted among slaughterhouse workers in contact with dromedaries. MERS-CoV S1 IgG reactivity was assessed using ELISA. Potential cross-reactivity with SARS-CoV-2 antibodies was excluded by comparing ELISA ODRs between MERS-CoV S1 and SARS-CoV-2 S1 assays. Neutralization tests (NT) were conducted using green fluorescent protein (GFP)–encoding vesicular stomatitis virus pseudoparticles (VSVpp) carrying MERS-CoV S protein from two clades. Testing was performed on seven serum samples at a 1:20 dilution. A plaque-reduction neutralization test (PRNT) based on MERS-CoV EMC/2012 was conducted.

    Results and discussion

    MERS-CoV RNA was detected in 1.3% of camels. The cumulative RNA positivity rate was found to be higher in September-October 2022 (5.0%) compared to January-March 2023 (2.3%). Incidence showed biphasic peaks in October 2022 and February 2023. Phylogenetic analysis revealed high similarity (>99.93% nucleotide identity) with MERS-CoV strains from Akaki, Ethiopia, in 2019. The sequences clustered within clade C2.2, which includes strains initially identified in Kenya in 2018, indicating three putative MERS-CoV outbreaks in Kenyan camels.

    MERS-CoV IgG levels had a median ODR of 2.14, with a seroprevalence of 80.76%. IgG levels were lowest in June and highest in March. A negative association was found between MERS-CoV IgG levels and RNA positivity. RNA-positivity was found to be negatively linked to the season. Compared to female camels, male camels showed a greater probability of being RNA-positive and a lower probability of being seropositive. Older animals (>3 years) had a higher (but statistically insignificant) seropositivity rate (86%) compared to animals ≤3 years (72%).

    MERS-CoV S1 IgG reactivity was detected in 14.6% of Isiolo abattoir workers. The absence of MERS-CoV S1 IgG reactivity was noted in a control cohort (n = 12) without camel exposure despite high SARS-CoV-2 S1 IgG levels (92%). Notably, one serum sample showed a VSVpp-NT 50–90% reduction of foci-forming units. Additionally, results from PRNT confirmed MERS-CoV seroconversion for the sample. None of the MERS-CoV ELISA-negative samples demonstrated neutralizing capacity in VSVpp-NT and PRNT assays.

    Conclusion

    In conclusion, the present study revealed a biphasic incidence of MERS-CoV in dromedary camels, potentially influenced by increased animal interactions during transport and seasonal factors. The evidence of human transmission in the study highlights the need for enhanced surveillance and preventive measures to mitigate zoonotic transmission risk. Further research is warranted to investigate the dynamics of MERS-CoV circulation and formulate strategies for potential disease control and prevention.

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  • New study pinpoints key markers for Long COVID diagnosis

    New study pinpoints key markers for Long COVID diagnosis

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    In a recent preprint* uploaded to the medRxiv server, an international team of researchers conducted a large-scale systems-level immunological screening of more than 1,000 confirmed COVID-19 patients to identify diagnostic markers of Long-term COVID-19. The analyses using multiple orthogonal detection methods reveal elevated serologic responses as a highlight of Long COVID and that its correlated memory CD8+ T cell clonal expansion is a more reliable and sensitive marker of the condition than conventional antigen (SARS-CoV-2 RNA and protein) detection approaches.

    Study: Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID. Image Credit: Lightspring / ShutterstockStudy: Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID. Image Credit: Lightspring / Shutterstock

    *Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

    COVID-19 and the need for Long COVID diagnosis

    The ongoing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused Coronavirus disease 2019 (COVID-19) viral pandemic is one of the worst in human memory, estimated to have infected more than 700 million individuals since its discovery in Wuhan, China, in late 2019. While global legislative policy and the widespread development and dissemination of anti-COVID-19 vaccines have substantially reduced the disease burden, with reports of vaccination efforts saving 70% of patients or more, survivors of the pandemic are plagued by a hitherto unknown condition – Long COVID.

    Also called the ‘Post COVID-19 condition’, ‘chronic COVID syndrome,’ and clinically, ‘post-acute sequelae of COVID-19 (PASC)’, Long COVID presents itself as perhaps the worst legacy of the pandemic. The now well-established yet poorly understood condition is characterized by the persistence or development of COVID-19-associated symptoms that may persist for months or even years following initial infection recovery. These symptoms include severe cognitive decline (brain fog), chronic fatigue, and multiple organ damage, resulting in significant economic and quality of life (QoL) losses in patients.

    Alarmingly, research has revealed that despite vaccination efforts substantially reducing adverse Long COVID outcomes, between 30 and 60% of all COVID-19 infections result in Long COVID, with an estimated 350+ million individuals suffering from the condition. Unfortunately, extensive global scientific efforts remain unable to elucidate the mechanisms underpinning Long COVID, hampering the development of diagnostic assays and clinical interventions for patients.

    About the study

    In the present study, researchers screened more than 1000 prospective patients enrolled at Long COVID clinics in Belgium and Sweden to elucidate the shared mechanisms of Long COVID pathology and subsequently develop a sensitive and reliable diagnostic test for the condition. Only subjects with a clinically confirmed mild or moderate COVID-19 infection were included. Severe cases were excluded due to overlapping symptoms with those of the post-intensive care syndrome.

    Patients without objective measures of disease-associated organ damage (e.g., magnetic resonance imaging [MRI], pulsatile arterial tonometry [EndoPAT], and postural orthostatic tachycardia syndrome [POTS]) were excluded. Inclusion and exclusion criteria resulted in a final sample cohort of 121 patients from Belgium (n = 31) and Sweden (n = 90).

    Experimental procedures included the enzyme-linked immunosorbent assay (ELISA) for detecting and measuring patients’ antibody responses against SARS-CoV-2. Since these standard ELISAs were not observed to elucidate differences in immunoglobulin A (IgA) and IgM despite clear case-convalescent control differences in IgG titers, single-molecule array (SIMOA) assays were employed. The SPEAR immunoassay was used to detect the presence of persistent SARS-CoV-2 spike proteins in patients’ plasma samples.

    Since these assays revealed that antigen responses were only depicted by about 10% of the study cohort, suggesting its unreliability and poor sensitivity as a diagnostic tool, researchers used a 51-parameter-panel mass cytometry assay to investigate possible immunological correlates. The Olinks assay was further conducted to measure levels of cytokines and other plasma proteins in patients’ plasma samples.

    “Autoantibodies to type-I IFN have been associated with life-threatening COVID-19 pneumonia due to impaired IFN-I-mediated inhibition of viral replication. Such autoantibodies increase in frequency with age, are more common in males than females for unknown reason, and could explain up to 20% of COVID-19 deaths. The reasons for the development of anti-cytokine autoantibodies are unknown in most cases, but most, if not all, patients with inborn errors of central tolerance due to AIRE deficiency in cis (APECED or APS1) or in trans (mutations of the alternative NF-kB pathway) all carry these autoantibodies and are highly susceptible to severe SARSCoV-2 infections.”

    To investigate the above, single-cell T-cell receptor (TCR) and message RNA (mRNA) sequencing of peripheral blood mononuclear cells (PBMCs) was carried out. Memory CD8 T cell TCR sequences were then clustered using the GLIPH methodology.

    Study findings

    The present study reveals that, while IgG response to SARS-CoV-2 spike (receptor binding domain [RDB]) proteins as measured by the SIMAO assay can be used as a sensitive Long COVID marker, IgA and IgM cannot due to their detection in ~10% of afflicted patients. This suggests that memory CD8+ T cells were restrained, and their clonal expansion is restricted by SARS-CoV-2, inconsistent with the previously hypothesized exhausted phenotype pathology.

    Strong and persistent Long COVID symptoms despite high IgG tirtes suggest differences between the initial and long-term adaptive responses of patients’ immunity to SARS-CoV-2.

    “A strong initial adaptive response might increase the chance of viral clearance and reduce the risk of Long COVID, while a sustained and elevated long-term response to SARSCoV-2 with elevated titers occur once a viral reservoir has been established leading to chronic antigen stimulation.”

    Results highlight that in Long COVID cases, the elevated serologic response was inversely correlated to expanding CD8+ T cell populations, elucidating the role of the restrained antiviral T cell response as a crucial component of Long COVID pathology. Current and future work aimed at understanding the genetic basis of this revelation may allow for the development of clinical therapeutics capable of treating this hitherto incurable condition.

    Conclusions

    The present study uses a combination of ELISA, SIMOA, and sequencing assays to investigate the associations between circulating immunoglobulin titers and Long COVID pathology, with the dual aim of elucidating Long COVID’s mechanism of action and progressing the discovery of a universal Long COVID diagnostic test. Their findings reveal that contrary to expectation, IgG titers in Long COVID patients increase following initial infection recovery, suggesting chronic antigen stimulation.

    IgA and IgM titers, in contrast, were extremely low and detectable in only 10% of cases, making them unreliable in Long COVID diagnosis.

    *Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

    Journal reference:

    • Preliminary scientific report.
      Lucie Rodriguez, Ziyang Tan, Lakshmi Kanth Tadepally, Jun Wang, Hugo Barcenilla, Zoe Swank, Fanglei Zuo, Hassan Abolhassani, Ana Jimena Pavlovitch-Bedzyk, Chunlin Wang, Laura Gonzalez, Constantin Habimana Mugabo, Anette Johnsson, Yang Chen, Anna James, Jaromir Mikes, Linn Kleberg, Christopher Sundling, Mikael Bjornson, Malin Nygren-Bonnier, Marcus Stahlberg, MIchael Runold, Sofia Bjorkander, Erik Melen, Isabelle Meyts, Johan Van Weyenbergh, Qiang Pan Hammarstrom, Mark M Davis, David R. Walt, Nils Landegren, COVID Human Genetic Effort, Alessandro Aiuti, Giorgio Casari, Jean-Laurent Casanova, MARC JAMOULLE, Judith Bruchfeld, Petter Brodin. Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID. medRxiv (2024), DOI – 10.1101/2024.02.11.24302636, https://www.medrxiv.org/content/10.1101/2024.02.11.24302636v1

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  • Study suggests patients with severe long COVID present with variable symptoms, do not cluster in relation to organs affected or immunological states

    Study suggests patients with severe long COVID present with variable symptoms, do not cluster in relation to organs affected or immunological states

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    A new preprint, recently uploaded to the medRxiv* preprint server, reports significantly associated findings that may help predict severe long COVID and understand what causes it.

    Study: Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID. Image Credit: Anucha Naisuntorn/Shutterstock.com
    Study: Restrained memory CD8+ T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID. Image Credit: Anucha Naisuntorn/Shutterstock.com

    *Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

    Background

    SARS-CoV-2 infection causes protean manifestations extending over a wide range of severity. In the most severe cases, multiorgan failure and death supervene, with underlying coagulation failure and hyperinflammation. The key factor is the occurrence of an antiviral type-1 interferon (IFN-1) response to infection of respiratory epithelial cells and antigen-presenting dendritic cells, as this is responsible for further events that limit viral replication. In addition, it allows immune clearance of the virus.

    A type of post-COVID sequel among children has been termed the Multisystem Inflammatory Syndrome in Children (MIS-C). The occurrence of this condition is associated with the persistence of the virus in the gut, perhaps linked to chronic T cell activation.

    The resemblance to superantigen-induced T cell activation did not escape notice, especially as a superantigen-like motif had already been reported in the SARS-CoV-2 spike protein with similarity to staphylococcal enterotoxin B. Coupled with potential genetic defects associated with MIS-C, the authors speculate a common origin for both long COVID and MIS-C.

    According to them, “disease tolerance, restrained antiviral T cell responses and viral persistence” comprise one such possibility. They believe that in select groups, such as children and women of reproductive age, efficient antiviral responses ensure mild infections by limiting systemic inflammation and T cell responses. On the flip side, this increases the odds of viral persistence and, thus of long COVID.

    Evidence for viral persistence is scanty, including the presence of viral antigens in blood and tissue samples and imaging reports, as well as finding continued somatic hypermutation in B cells specific to this virus. Again, vaccination against COVID-19 reduces the risk of long COVID, as does early antiviral therapy, supporting the hypothesis that this sequel results from viral persistence.

    The current report centers on patients who had mild to moderate COVID-19 and later developed severe long COVID.  

    What did the study show?

     The scientists examined only patients with documented mild to moderate SARS-CoV-2 infection who had not been hospitalized over a thousand of them. From these, they selected those who had evidence of organ damage to the heart, blood vessels, autonomic nervous system, hyperventilation, or changes in computerized tomography (CT) of the lungs.

    These were chosen since they provided objective proof of organ damage, supporting the diagnosis of severe long COVID. They found ~120 cases, almost 90% being females with the mean age being 48 years.

    They found that there is no common set of symptoms, signs of organ damage, or characteristic immunological profile in patients who develop long COVID. However, serum antibody responses were markedly higher in these patients compared to those who recovered rapidly. This is a sign of persistent antigen stimulation, especially as these cases were sampled long after the acute infection.

    When viral RNA and protein antigens were looked for in plasma samples, using an array of independent testing methods, the researchers found that only a subset of patients were positive for viral antigens by any of the methods used. There was little overlap in the results between different assays. This indicates that blood tests for viral persistence may not yield uniform results, and the finding of elevated antibody levels is a more sensitive marker of long COVID.

    The failure to detect antigens by all assays could either reflect the decreased sensitivity of the tests or the fact that the virus harbored in the tissue reservoirs may not leak the antigens into the bloodstream. It is unlikely that failure of viral persistence is the reason, given the persistent increase in anti-SARS-CoV-2 IgG responses observed in multiple cohorts.

    They also found certain monocyte subsets and plasma proteins associated with an ongoing innate immune response at elevated levels. Such elevations were in proportion to increased immunoglobulin G (IgG) antibody titers, a marker of persistent inflammation.

    In contrast, there was a failure of expansion of cytotoxic memory CD8+ T cells targeting SARS-CoV-2. The frequency of such clones decreases as antibody levels rise.

    This suggests that individuals who fail to mount a clonally expanded memory CD8+ T cell response to SARS-CoV-2 develop a viral reservoir with persistent antigen.”

    The researchers did not find autoantibodies to IFN-1 in these patients. However, these have been found in life-threatening COVID-19-associated pneumonia and account at least in part for one in five deaths due to COVID-19 by inhibiting IFN-1-mediated suppression of viral replication.

    This indicates that the underlying mechanism of long COVID is viral persistence, with impaired CD8+ T cell responses being the norm, rather than T cell exhaustion, as some scientists have suggested earlier to be characteristic of severe long COVID.

    What are the implications?

    The study suggests that the finding of elevated SARS-CoV-2-specific IgG sensitively identifies long COVID mounted against the spike antigen. Secondly, this is likely to be the result of viral persistence with chronic antigen stimulation.

    Those patients who respond strongly to the initial infection via an adaptive immune response likely clear the virus rapidly and have a lower chance of long COVID. In contrast, if a viral reservoir is established, chronic stimulation by viral antigens leads to a long-term elevation of anti-SARS-CoV-2 IgG.

    The researchers continue to seek the reason for the failure of viral clearance in some patients leading to long COVID. Until then, prolonged administration of antivirals may be the best way to treat these patients by removing the viral reservoir.

    *Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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