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Tag: SARS

  • SARS-CoV-2-associated ARDS can damage the heart without direct infection

    SARS-CoV-2-associated ARDS can damage the heart without direct infection

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    SARS-CoV-2, the virus that causes COVID-19, can damage the heart even without directly infecting the heart tissue, a National Institutes of Health-supported study has found. The research, published in the journal Circulation, specifically looked at damage to the hearts of people with SARS-CoV2-associated acute respiratory distress syndrome (ARDS), a serious lung condition that can be fatal. But researchers said the findings could have relevance to organs beyond the heart and also to viruses other than SARS-CoV-2.

    Scientists have long known that COVID-19 increases the risk of heart attack, stroke, and Long COVID, and prior imaging research has shown that over 50% of people who get COVID-19 experience some inflammation or damage to the heart. What scientists did not know is whether the damage occurs because the virus infects the heart tissue itself, or because of systemic inflammation triggered by the body’s well-known immune response to the virus.

    This was a critical question and finding the answer opens up a whole new understanding of the link between this serious lung injury and the kind of inflammation that can lead to cardiovascular complications. The research also suggests that suppressing the inflammation through treatments might help minimize these complications.”


    Michelle Olive, Ph.D., Associate Director, Basic and Early Translational Research Program at the National Heart, Lung, and Blood Institute (NHLBI)

    To reach their findings, the researchers focused on immune cells known as cardiac macrophages, which normally perform a critical role in keeping the tissue healthy but can turn inflammatory in response to injury such as heart attack or heart failure. The researchers analyzed heart tissue specimens from 21 patients who died from SARS-CoV-2-associated ARDS and compared them with specimens from 33 patients who died from non-COVID-19 causes. They also infected mice with SARS-CoV-2 to follow what happened to the macrophages after infection.

    In both humans and mice, they found the SARS-CoV-2 infection increased the total number of cardiac macrophages and also caused them to shift from their normal routine and become inflammatory.

    When macrophages are no longer doing their normal jobs, which includes sustaining the metabolism of the heart and clearing out harmful bacteria or other foreign agents, they weaken the heart and the rest of the body, said Matthias Nahrendorf, M.D., Ph.D., professor of Radiology at Harvard Medical School and senior author on the study.

    The researchers then designed a study in mice to test whether the response they observed happened because SARS-CoV-2 was infecting the heart directly, or because the SARS-CoV-2 infection in the lungs was severe enough to render the heart macrophages more inflammatory. This study mimicked the lung inflammation signals, but without the presence of the actual virus. The result: even in the absence of a virus, the mice showed immune responses strong enough to produce the same heart macrophage shift the researchers observed both in the patients who died of COVID-19 and the mice infected with SARS-CoV-2 infection.

    “What this study shows is that after a COVID infection, the immune system can inflict remote damage on other organs by triggering serious inflammation throughout the body – and this is in addition to damage the virus itself has directly inflicted on the lung tissue,” said Nahrendorf. “These findings can also be applied more generally, as our results suggest that any severe infection can send shockwaves through the whole body.”

    The research team also found that blocking the immune response with a neutralizing antibody in the mice stopped the flow of inflammatory cardiac macrophages and preserved cardiac function. While they have yet to test this in humans, Nahrendorf said a treatment like this could be used as a preventive measure to help COVID-19 patients with pre-existing conditions, or people who are likely to have more severe outcomes from SARS-CoV-2 associated ARDS.

    Source:

    NIH/National Heart, Lung and Blood Institute

    Journal reference:

    Grune, J., et al. (2024) Virus-induced ARDS causes cardiomyopathy through eliciting inflammatory responses in the heart. Circulation. doi.org/10.1161/CIRCULATIONAHA.123.066433.

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  • Severity of current SARS-CoV-2 variants is not linked to the number of mutations

    Severity of current SARS-CoV-2 variants is not linked to the number of mutations

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    New research from UNC Charlotte’s Center for Computational Intelligence to Predict Health and Environmental Risks (CIPHER) has found that the two most prevalent strains of the virus that cause COVID-19, SARS-CoV-2 variants BA.2.86 and JN.1, are not significantly better than their predecessor Omicron at evading immune responses and causing infections despite having a high number of mutations compared to previous variants.

    When first identified, Omicron offshoots BA.2.86 and its close relative JN.1 raised significant public health concerns. These concerns were tied to the fact that the original Omicron variant was highly mutated, resulting in both immune evasion and breakthrough infection, as well as more infectious and highly-mutated compared to earlier variants.

    There was some speculation that large numbers of new mutations in BA.2.86 and JN.1 conferred a greater ability of these variants to evade the human immune system and be more transmissible. Extensive computational analyses conducted by a team of UNC Charlotte scholars and students determined that these variants only had small, statistically insignificant changes in immune evasion and transmissibility infection capacity compared to earlier variants, including Omicron.

    These results really surprised me. The fact that Omicron, with its large set of mutations, led to greater immune evasion and a surge in cases and hospitalizations was predictable. However, BA.2.86 and JN.1 have yet another large set of mutations, and while we have seen some signals of increased prevalence of these two variants in wastewater and genomic surveillance, there has not been an accompanying large surge in cases or hospital burden.”


    Daniel Janies, Co-Director of CIPHER and the Carol Grotnes Belk Distinguished Professor of Bioinformatics and Genomics in the College of Computing and Informatics

    To assess the immune evasion of BA.2.86 and JN.1, the UNC Charlotte research team performed an extensive in silico analysis on the Receptor Binding Domain (RBD; the region of the viral genome against which vaccines are designed) of SARS-CoV-2, comparing the two newer variants to previous variants to calculate the relative binding affinity of neutralizing antibodies to the RBD from vaccinated patients, infected patients and therapeutic sources. In addition to antibody analysis, researchers calculated the relative binding affinity of BA.2.86 and JN.1 to Angiotensin Converting Enzyme-2 (ACE2) in comparison to previous variants.

    The team found minor changes in binding affinity for neutralizing antibodies and ACE2 for BA.2.86 and JN.1 in comparison to previous SARS-CoV-2 variants. However, those changes were not statistically significant. Therefore, they concluded that BA.2.86 and JN.1 have no significant increase in immune evasion or infection capacity to previous variants. In explaining their results, the researchers caution that genomic surveillance, which counts mutations or relative prevalence of a variant, does not necessarily reveal the functional and health impacts of the variant.

    In a study awaiting publication outlining their research, the team discusses the benefits of their approach to understand the function of variants and the need for future studies to assess variation outside of the RBD for future analysis. Future studies in this area will benefit from an increased focus on antibodies derived from memory B-cells that produce antibodies in response to SARS-CoV-2.

    “In patients whose immune systems have been exposed to a previous Omicron variant, memory B-cells may provide significant protection for the newer Omicron variants BA.2.86 and JN.1,” said Shirish Yasa, a current Charlotte bioinformatics and computer science senior who helped conduct this research. “This protection conferred by memory B-cell-derived antibodies is a process not yet well studied. An increase in Omicron targeting memory B-cells via vaccination and prior infection could be a significant factor in the overall reductions we have seen in hospitalizations and deaths for patients exposed to the descendents of the original Omicron variant.”

    This research contributes to the functional understanding of SARS-CoV-2 variants BA.2.86 and JN.1, building on the studies of genomic surveillance. Moreover, this UNC Charlotte effort has introduced new methodologies for functional computational immunology, which will help in the ongoing efforts to mitigate the consequences of the COVID-19 pandemic.

    Source:

     University of North Carolina at Charlotte

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  • Health workers fear it’s profits before protection as CDC revisits airborne transmission

    Health workers fear it’s profits before protection as CDC revisits airborne transmission

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    Four years after hospitals in New York City overflowed with covid-19 patients, emergency physician Sonya Stokes remains shaken by how unprepared and misguided the American health system was.

    Hospital leadership instructed health workers to forgo protective N95 masks in the early months of 2020, as covid cases mounted. “We were watching patients die,” Stokes said, “and being told we didn’t need a high level of protection from people who were not taking these risks.”

    Droves of front-line workers fell sick as they tried to save lives without proper face masks and other protective measures. More than 3,600 died in the first year. “Nurses were going home to their elderly parents, transmitting covid to their families,” Stokes recalled. “It was awful.”

    Across the country, hospital leadership cited advice from the Centers for Disease Control and Prevention on the limits of airborne transmission. The agency’s early statements backed employers’ insistence that N95 masks, or respirators, were needed only during certain medical procedures conducted at extremely close distances.

    Such policies were at odds with doctors’ observations, and they conflicted with advice from scientists who study airborne viral transmission. Their research suggested that people could get covid after inhaling SARS-CoV-2 viruses suspended in teeny-tiny droplets in the air as infected patients breathed.

    But this research was inconvenient at a time when N95s were in short supply and expensive.

    Now, Stokes and many others worry that the CDC is repeating past mistakes as it develops a crucial set of guidelines that hospitals, nursing homes, prisons, and other facilities that provide health care will apply to control the spread of infectious diseases. The guidelines update those established nearly two decades ago. They will be used to establish protocols and procedures for years to come.

    “This is the foundational document,” said Peg Seminario, an occupational health expert and a former director at the American Federation of Labor and Congress of Industrial Organizations, which represents some 12 million active and retired workers. “It becomes gospel for dealing with infectious pathogens.”

    Late last year, the committee advising the CDC on the guidelines pushed forward its final draft for the agency’s consideration. Unions, aerosol scientists, and workplace safety experts warned it left room for employers to make unsafe decisions on protection against airborne infections.

    “If we applied these draft guidelines at the start of this pandemic, there would have been even less protection than there is now — and it’s pretty bad now,” Seminario said.

    In an unusual move in January, the CDC acknowledged the outcry and returned the controversial draft to its committee so that it could clarify points on airborne transmission. The director of the CDC’s National Institute for Occupational Safety and Health asked the group to “make sure that a draft set of recommendations cannot be misread to suggest equivalency between facemasks and NIOSH Approved respirators, which is not scientifically correct.”

    The CDC also announced it would expand the range of experts informing their process. Critics had complained that most members of last year’s Healthcare Infection Control Practices Advisory Committee represent large hospital systems. And about a third of them had published editorials arguing against masks in various circumstances. For example, committee member Erica Shenoy, the infection control director at Massachusetts General Hospital, wrote in May 2020, “We know that wearing a mask outside health care facilities offers little, if any, protection from infection.”

    Although critics are glad to see last year’s draft reconsidered, they remain concerned. “The CDC needs to make sure that this guidance doesn’t give employers leeway to prioritize profits over protection,” said Jane Thomason, the lead industrial hygienist at the union National Nurses United.

    She’s part of a growing coalition of experts from unions, the American Public Health Association, and other organizations putting together an outside statement on elements that ought to be included in the CDC’s guidelines, such as the importance of air filtration and N95 masks.

    But that input may not be taken into consideration.

    The CDC has not publicly announced the names of experts it added this year. It also hasn’t said whether those experts will be able to vote on the committee’s next draft — or merely provide advice. The group has met this year, but members are barred from discussing the proceedings. The CDC did not respond to questions and interview requests from KFF Health News.

    A key point of contention in the draft guidance is that it recommends different approaches for airborne viruses that “spread predominantly over short distances” versus those that “spread efficiently over long distances.” In 2020, this logic allowed employers to withhold protective gear from many workers.

    For example, medical assistants at a large hospital system in California, Sutter Health, weren’t given N95 masks when they accompanied patients who appeared to have covid through clinics. After receiving a citation from California’s occupational safety and health agency, Sutter appealed by pointing to the CDC’s statements suggesting that the virus spreads mainly over short distances.

    A distinction based on distance reflects a lack of scientific understanding, explained Don Milton, a University of Maryland researcher who specializes in the aerobiology of respiratory viruses. In general, people may be infected by viruses contained in someone’s saliva, snot, or sweat — within droplets too heavy to go far. But people can also inhale viruses riding on teeny-tiny, lighter droplets that travel farther through the air. What matters is which route most often infects people, the concentration of virus-laden droplets, and the consequences of getting exposed to them, Milton said. “By focusing on distance, the CDC will obscure what is known and make bad decisions.”

    Front-line workers were acutely aware they were being exposed to high levels of the coronavirus in hospitals and nursing homes. Some have since filed lawsuits, alleging that employers caused illness, distress, and death by failing to provide personal protective equipment.

    One class-action suit brought by staff was against Soldiers’ Home, a state-owned veterans’ center in Holyoke, Massachusetts, where at least 76 veterans died from covid and 83 employees were sickened by the coronavirus in early 2020.

    “Even at the end of March, when the Home was averaging five deaths a day, the Soldiers’ Home Defendants were still discouraging employees from wearing PPE,” according to the complaint.

    It details the experiences of staff members, including a nursing assistant who said six veterans died in her arms. “She remembers that during this time in late March, she always smelled like death. When she went home, she would vomit continuously.”

    Researchers have repeatedly criticized the CDC for its reluctance to address airborne transmission during the pandemic. According to a new analysis, “The CDC has only used the words ‘COVID’ and ‘airborne’ together in one tweet, in October 2020, which mentioned the potential for airborne spread.’”

    It’s unclear why infection control specialists on the CDC’s committee take a less cautious position on airborne transmission than other experts, industrial hygienist Deborah Gold said. “I think these may be honest beliefs,” she suggested, “reinforced by the fact that respirators triple in price whenever they’re needed.”

    Critics fear that if the final guidelines don’t clearly state a need for N95 masks, hospitals won’t adequately stockpile them, paving the way for shortages in a future health emergency. And if the document isn’t revised to emphasize ventilation and air filtration, health facilities won’t invest in upgrades.

    “If the CDC doesn’t prioritize the safety of health providers, health systems will err on the side of doing less, especially in an economic downturn,” Stokes said. “The people in charge of these decisions should be the ones forced to take those risks.”




    Kaiser Health NewsThis article was reprinted from khn.org, a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – the independent source for health policy research, polling, and journalism.

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  • Certain genes slash severity and death risk in older men

    Certain genes slash severity and death risk in older men

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    In a recent study published in The Journal of Infectious Diseases, researchers investigated the inflammation outcomes of three different Interleukin-1 receptor antagonist gene (IL1RN) single-nucleotide variants (SNVs) in acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection patients. Their retrospective study included almost 2,600 confirmed severe coronavirus disease 2019 (COVID-19) patients and showed that the IL1RN CTA haplotype and its rs419598 C/C SNV dramatically attenuated COVID-19-associated hyperinflammation, a characteristic of severe SARS-CoV-2 infections.

    Observed outcomes were substantially improved in men compared to women, with men depicting 15% reduced mortality over women with the same SNV. These findings were most extreme for older men, with patients with the rs419598 C/C SNV above the age of 74 presenting 80% less mortality risk than their non-SNV-expressing age-matched counterparts. This study is one of the first to elucidate the genetic determinants of COVID-19 pathology and may form the basis for personalized future interventions against the disease.

    Study: Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19. Image Credit: Adao / ShutterstockStudy: Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19. Image Credit: Adao / Shutterstock

    COVID-19 and the dangers of CRS

    The coronavirus disease 2019 (COVID-19) represents one of the worst pandemics in human history, responsible for almost 7 million deaths worldwide and leaving hundreds of millions of survivors with long-lasting clinical symptoms. In severe cases, the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may result in multiorgan failure, acute respiratory distress syndrome (ARDS), and even death in 10-20% of affected patients.

    Research has shown that severe COVID-19 symptoms are often associated with elevated plasma cytokine levels, especially those of interleukin 1β (IL-1β), IL-2, and IL-6. Unfortunately, a number of immunotherapy drugs, including those used to treat COVID-19, have been implicated in the overexpression of these ILs, a condition similar to cytokine release syndrome (CRS). Previous work by the present research group identified that IL1RN haplotypes containing the rs419598, rs315952, and rs9005 single-nucleotide variants (SNVs) could alter osteoarthritis and rheumatoid arthritis severity by attenuating hyperinflammation.

    Unfortunately, the role of genetics in COVID-19 pathology remains poorly understood. The present study aims to shine a light on this knowledge gap by investigating the role of IL1RN SNP in moderate-to-severe COVID-19 infections.

    About the study

    Previous research by the current group identified the associations of IL1RN genetic variants with osteoarthritis and rheumatoid arthritis outcomes. It revealed that three SNVs (rs419598, rs315952, and rs9005) improved disease outcomes via hyperinflammation reduction mechanisms. The present study aims to investigate if the same genetic variants could improve COVID-19 outcomes due to the central role of hyperinflammation in severe COVID-19 pathology.

    The study is a retrospective, observational study comprising data from adult (19+) patients admitted to Tisch Hospital, New York, United States, between March 2010 and March 2021. The cytokine profiles of these patients were compared against healthy age, sex, and body mass index (BMI)-matched controls without a clinical history of COVID-19 exposure. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays were used to confirm COVID-19 status and severity. Data sources comprised sociodemographic (sex, age, race, and ethnicity) and medical data obtained from hospital records and discarded COVID-19 blood samples (for plasma extraction). Data generation included whole-genome sequences (low coverage) of participants’ blood. The gencove.org database was used to annotate common SNV genotypes for each sequenced sample.

    Three IL1RN genotypes, namely rs419598, rs315952, and rs9005, formed the focus of this study and were extracted from patients’ plasma samples during routine COVID-19 care. However, since multiple cytokines of interest were not included in routine care, plasma samples from 359 randomly selected study participants and their demography-matched controls were additionally extracted and subjected to a multiplex enzyme-linked immunosorbent assay (ELISA) assay.

    “Plasma cytokines IL-1β, IL-2, and IL-6 were determined by a test developed by ARUP Laboratories (Salt Lake City, UT) and approved by the New York State Department of Health.”

    Summary statistics were used to collate and analyze demographic variables and mortality statuses categorized by sex, race/ethnicity, and age. Univariate parametric tests were computed to evaluate CRS and mortality outcomes for each category. Comparisons between the mortality risks of different genotypes were conducted using multivariate logistic regressions, adjusting for sex and age.

    Study findings

    The present study included records from 2,589 hospitalized patients and an equal number of age, sex, and BMI-matched controls. Study participants presented a mean age of 61.2 years, an average BMI of 30.43, and comprised 53.3% male individuals.

    “IL1RN rs419598, rs315952, and rs9005 genotype data were available for all patients. Biomarkers noted in the clinical electronic hospital record (EHR) for IL-1β, IL-2, and IL-6 were available for 642, 645, and 1229 subjects, respectively, whereas other plasma inflammatory markers were available for more than 2000 subjects.”

    ELISA and cytokine analyses revealed that, compared to healthy control, COVID-19 patients displayed significantly elevated levels of cytokines (IL-1α, IL-5, IL-8, IL-17, IL-1β, IL-2, IL-1Ra, IL-6, tumor necrosis factor-α [TNF-α], interferon-α, and vascular endothelial growth factor [VEGF]). Alarmingly, levels of IL-6, IL-1Ra, IL-8, and IL-10 were found to be more than 10 times higher than baseline controls’ values. Inflammatory markers, including CRP, procalcitonin, D-dimer, and ferritin, were similarly heightened.

    Of the included patients, 397 (15.3%) died during treatment, with age (direct), sex (male at higher risk), and BMI (direct) showing associations with COVID-19-associated mortality.

    “RS-associated inflammatory biomarkers were elevated in both patients who survived and died; however, deceased patients had significantly higher levels of IL-6, CRP, procalcitonin, ferritin, and D-dimer, as well as reduced levels of complement components C3 and C4.”

    Surprisingly, carriers of the IL1RN CTA-1/2 haplotype (either or two copies of the CTA haplotype) displayed substantially reduced inflammatory marker concentrations (except IL-1Ra, which was increased in these patients) compared to patients without the genotype. Encouragingly, the CTA haplotype was found to confer a 40% reduction in COVID-19-associated mortality risk in men above the age of 74. However, no associations with BMI were revealed. When evaluating each IL1RN CTA SNV individually, rs419598 C/C SNV patients exhibited substantially reduced inflammatory marker concentrations compared to their C/T or T/T counterparts.

    Comparison between men and women reveals that, while most biomarker and mortality outcomes are indistinguishable across the sexes, IL1RN rs419598 C/C SNV was found to be associated with a decreased trend in mortality in men of all included age groups. In men above the age of 74, especially, this genotype was associated with an 80% decline in mortality, highlighting the role of hyperinflammation in severe COVID-19 progression.

    Conclusions

    The present study highlights that the IL1RN CTA haplotype, especially in combination with the rs419598 C/C genotype, substantially reduced CRS in patients (irrespective of sex) in severe COVID-19 infections and substantially reduced mortality in men.  

    “We show that concomitant with decreased proinflammatory cytokine production, the IL1RN CTA haplotype and rs419598 C/C SNV are associated with increased levels of its anti-inflammatory gene product IL-1Ra. Our data provide genetic evidence that activation of the inflammasome and the IL-1 pathway is proximal in the systemic cytokine inflammatory cascade. Its regulation by IL-1Ra, an endogenous anti-inflammatory protein, and potential crosstalk with IFN require further elucidation to advance the understanding and treatment of SARS-CoV-2 infection.”

    Journal reference:

    • Attur, M., Petrilli, C., Adhikari, S., Iturrate, E., Li, X., Tuminello, S., Hu, N., Chakravarti, A., Beck, D., & Abramson, S. B. Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19. The Journal of Infectious Diseases, DOI – 10.1093/infdis/jiae031, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiae031/7625543

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  • COVID-19 vaccine associated with reduced risk of cardiac and clot-related complications after SARS-CoV-2 infection

    COVID-19 vaccine associated with reduced risk of cardiac and clot-related complications after SARS-CoV-2 infection

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    The risk of cardiac and clot-related complications following COVID-19 is substantially reduced in people who receive the COVID-19 vaccination compared with unvaccinated individuals, reports an observational study published online in the journal Heart.

    COVID-19 vaccines proved to be highly effective in reducing the severity of acute SARS-CoV-2 infection, COVID-19-related hospital admission and death.

    And while some COVID-19 vaccines were associated with increased risk of rare but serious complications, such as blood clots and heart inflammation (myocarditis), the risk of these complications was substantially higher after SARS-CoV-2 infection.

    Some studies have suggested that vaccination could protect against these complications of COVID-19, but most did not include long-term complications and were focused on specific populations.

    To address this, researchers set out to study the association between COVID-19 vaccination and the risk of post-COVID-19 cardiac and thromboembolic complications using population data for the UK, Spain and Estonia which included 10.17 million vaccinated people and 10.39 million unvaccinated people.

    Individuals who were vaccinated received either an adenovirus-based vaccine (Oxford/AstraZeneca or Janssen) or one of the mRNA vaccines (BioNTech/Pfizer or Moderna).

    The researchers identified cases of cardiac and thromboembolic complications in the first year after SARS-CoV-2 infection and recorded them according to four post-infection time windows: 0-30, 31-90, 91-180 and 181-365 days after infection.

    A range of potentially influential factors, such as age, sex and pre-existing conditions including chronic lung disease, diabetes, heart disease and a history of blood clots were accounted for in the analysis to minimise bias.

    The results show that COVID-19 vaccination was associated with reduced risks of heart failure, venous thromboembolism (clot within the veins of a limb) and arterial thrombosis/thromboembolism (blood clot in the artery) for up to a year after SARS-CoV-2 infection.

    Reduced risk of other complications, such as ventricular arrhythmia/cardiac arrest (heart attack), myocarditis/pericarditis were also seen but only in the acute phase (first 30 days after infection).

    Compared with unvaccinated individuals, having COVID-19 vaccination was associated with reduced risks of venous thromboembolism by 78%, arterial thrombosis/thromboembolism by 47% and heart failure by 55% in the first 30 days after SARS-CoV-2 infection.

    As time progressed, the protective effects of vaccination waned, but remained at 47%, 28%, and 39% respectively at 91-180 days after infection and 50%, 38%, and 48% respectively at 181-365 days.

    This is an observational study, so can’t establish cause and effect, and the authors highlight some limitations including the inherent data quality concerns and risk of bias with use of real-world data, and potential under-reporting of post-COVID-19 complications.

    However, state-of-the-art statistical methods were used to deal with these limitations and results were consistent across all databases, which they say highlights the robustness and replicability of the findings.

    As such, they conclude, “Our analyses showed a substantial reduction of risk (42-82%) for thromboembolic and cardiac events in the acute phase of COVID-19 associated with vaccination.”

    They add, “Reduced risk in vaccinated people lasted for up to 1 year for post-COVID-19 venous thromboembolism, arterial thrombosis/thromboembolism and heart failure, but not clearly for other complications.”

    The authors suggest that the protective effects of vaccination are “consistent with known reductions in disease severity following breakthrough versus unvaccinated SARS-CoV-2 infection” and say further research is needed on the possible waning of the effect over time and on the impact of booster vaccination.

    Source:

    Journal reference:

    Mercadé-Besora, N., et al. (2024). The role of COVID-19 vaccines in preventing post-COVID-19 thromboembolic and cardiovascular complications. Heart. doi.org/10.1136/heartjnl-2023-323483.

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  • BU study reveals key to combating high-risk neuroblastoma

    BU study reveals key to combating high-risk neuroblastoma

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    The MYCN oncoprotein (proteins related to the growth of cancer cells) plays a key role in starting, advancing and making it difficult to treat various human cancers. When MYCN is overactive, especially in high-risk neuroblastoma (childhood cancer often found in the adrenal glands), the tumors become less responsive to immunotherapy-;a treatment that uses the body’s immune system to fight cancer. Still, recognition of this problem has not led to any effective strategies to tackle this problem.

    In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers found that MYCN selectively increases the levels of a signaling molecule, CKLF, in neuroblastoma cells to suppress anti-tumor immune responses and promote tumor aggressiveness.

    As scientists, we are looking for ways to make these less responsive tumors more receptive to immunotherapy to increase its effectiveness. Understanding how tumor cells utilize this molecule to communicate with immune cells will facilitate the development of effective immunotherapeutic strategies to provide more effective treatments with fewer toxicities for children with high-risk neuroblastoma.”


    Hui Feng, MD, PhD, corresponding author, associate professor of pharmacology, physiology & biophysics, Boston University School of Medicine

    The researchers studied an experimental model, clinical patient samples, and in-vitro cell culture. The experimental models of neuroblastoma with and without overexpression of the signaling molecule, CKLF, were compared for their ability to increase tumor aggression through the suppression of anti-tumor immune responses.

    According to Xiaodan Qin, PhD, the first author of the study and a research scientist in the Feng Lab, the research is critical to understanding the mechanisms by which tumor cells induce a tumor microenvironment that compromises the function of immune cells, and it uncovered additional therapeutic approaches to evoke anti-tumor immune responses. “The long-term goal of this research is to uncover effective drugs that are much less toxic than chemotherapy and radiotherapy for treating high-risk neuroblastoma and perhaps other types of MYCN-driven childhood cancers,” Feng says.

    The findings appear online in Science Advances.

    Source:

    Boston University School of Medicine

    Journal reference:

    Qin, X., et al. (2024). CKLF instigates a “cold” microenvironment to promote MYCN-mediated tumor aggressiveness. Science Advances. doi.org/10.1126/sciadv.adh9547.

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  • Long COVID manifests as a post-viral syndrome indistinguishable from other respiratory illnesses

    Long COVID manifests as a post-viral syndrome indistinguishable from other respiratory illnesses

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    Long COVID appears to manifest as a post-viral syndrome indistinguishable from seasonal influenza and other respiratory illnesses, with no evidence of increased moderate-to-severe functional limitations a year after infection, according to new research being presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024) in Barcelona, Spain (27-30 April).

    The study by Queensland Health researchers suggests that in the highly vaccinated population of Queensland exposed to the Omicron variant, long COVID’s impact on the health system is likely to stem from the sheer number of people infected with SARS-CoV-2 within a short period of time, rather than the severity of long COVID symptoms or functional impairment.

    The findings add to previous research by the same authors and published in BMJ Public Health which found no difference in ongoing symptoms and functional impairment when COVID-19 was compared with influenza,12 weeks post infection.

    Rates of long COVID in Australia are low due to high vaccination rates upon easing of COVID restrictions and the population’s subsequent exposure to the Omicron variant. Symptoms reported with the illness include fatigue, brain fog, cough, shortness of breath, change to smell and taste, dizziness, and rapid or irregular heartbeat.

    To understand more about the impact of long COVID on the Australian state of Queensland, researchers surveyed 5,112 symptomatic individuals aged 18 years and older, comprising those with PCR-confirmed infection for COVID-19 (2,399 adults) and those who were PCR negative for COVID-19 (2,713 adults: 995 influenza positive and 1,718 PCR negative for both but symptomatic with a respiratory illness) between 29 May and 25 June 2022.

    Laboratory reporting for COVID-19 and influenza is mandated upon PCR test request under Queensland’s public health legislation, with the results recorded in the Queensland Department of Health’s Notifiable Conditions System.

    A year after their PCR test, in May and June 2023, participants were asked about ongoing symptoms and the degree of functional impairment using a questionnaire delivered by SMS link.

    Overall, 16% (834/5,112) of all respondents reported ongoing symptoms a year later, and 3.6% (184) reported moderate-to-severe functional impairment in their activities of daily life.

    After controlling for influential factors including age, sex, and First Nation status, the analysis found no evidence that COVID-19 positive adults were more likely to have moderate-to-severe functional limitations a year after their diagnosis than symptomatic adults who were negative for COVID-19 (3.0% vs 4.1%).

    Moreover, results were similar when compared with the 995 symptomatic adults who had influenza (3.0% vs 3.4%).

    Interestingly, the analysis also found that those who were more likely to report moderate-to-severe functional impairment were those aged 50 years or older, and those who had symptoms of dizziness, muscle pain, shortness of breath, post-exertional malaise, and fatigue.

    In health systems with highly vaccinated populations, long COVID may have appeared to be a distinct and severe illness because of high volumes of COVID-19 cases during the pandemic. However, we found that the rates of ongoing symptoms and functional impairment are indistinguishable from other post-viral illnesses. These findings underscore the importance of comparing post-COVID-19 outcomes with those following other respiratory infections, and of further research into post-viral syndromes.”


    Dr. John Gerrard, Queensland’s Chief Health Officer

    He adds, “Furthermore, we believe it is time to stop using terms like ‘long COVID’. They wrongly imply there is something unique and exceptional about longer term symptoms associated with this virus. This terminology can cause unnecessary fear, and in some cases, hypervigilance to longer symptoms that can impede recovery.”

    The authors caution that the findings are associations and do not represent prevalence. They point to several limitations, including that participants who were hospitalised or had pre-existing illness were not identifiable within the cohort. They also note that the risk of long COVID has been lower during the Omicron wave compared with other SARS-CoV-2 variants, and because 90% of people in Queensland were vaccinated when Omicron emerged, the lower severity of long COVID could be due to vaccination and/or the variant.

    Source:

    European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024)

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  • New drug candidate designed at the atomic level could help halt emerging SARS-CoV-2 variants

    New drug candidate designed at the atomic level could help halt emerging SARS-CoV-2 variants

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    Although COVID-19 has faded from the headlines, SARS-CoV-2 – the coronavirus behind the pandemic – is still rampantly infecting people around the world. Public health officials fear as the virus continues to evolve, it will eventually hit upon a diabolical mutation that renders current treatments ineffective, triggering a new wave of severe infection and social disruption.

    In pursuit of new therapies to avoid this dark fate, researchers at Stanford have now unveiled a compound that measures up as a potentially powerful anti-coronavirus drug, detailed in a paper published March 13 in Science Translational Medicine. Dubbed ML2006a4, the compound works in the same way as Paxlovid – the most effective oral drug available to date – by binding to coronavirus particles and preventing the virus from making copies of itself. Compared to Paxlovid, though, ML2006a4 binds more tightly and durably, courtesy of the Stanford team custom-crafting the compound atom-by-atom.

    In preclinical experiments, the compound prevented deadly infections in mice at a superior rate compared to Paxlovid. In addition, the new compound is potent enough that it could likely be formulated without an additional component present in Paxlovid that poses severe drug interaction concerns. Importantly, ML2006a4 also performed well against coronavirus variants that have already evolved degrees of resistance to Paxlovid, suggesting the compound’s honed affinity makes it less vulnerable to mutant virus strains.

    At this point entering the fifth year of the pandemic, Paxlovid is our only really good drug against SARS-CoV-2, but it’s proven fairly easy for the virus to evolve resistance to it. As new waves of coronavirus keep crashing down, we need to have alternative drugs that are more tolerant of mutations and not as easy for the virus to defeat.”


    Michael Lin, senior author of the study, associate professor of neurobiology and of bioengineering in the schools of Medicine and Engineering and a member of Stanford Bio-X

    For the study, Lin worked closely with lead author Michael Westberg, now an assistant professor at Aarhus University in Denmark. From 2018 until 2022, Westberg worked in Lin’s lab as a visiting scholar at Stanford Bio-X, funded by the Novo Nordisk Foundation, through a joint program designed to strengthen international collaborations and the exchange of scientific expertise between Stanford and Denmark.

    Atomic-level precision

    Before the pandemic outbreak in 2020, Lin’s lab had already been investigating the broad class of drugs known as viral protease inhibitors. These drugs target protease enzymes that viruses need for disassembling bulky viral proteins as part of their replication cycle. Like a key fitting into a lock, protease inhibitors occupy the spaces, or active sites, where proteases normally link up with those bulky proteins, thus nipping replication in the bud.

    Specifically, the Stanford researchers had gained familiarity with hepatitis C virus protease, which has similarities to coronavirus versions. Although Westberg had come to Stanford to work on other projects, the global emergency prompted a pivot. “When the pandemic hit, we asked if we could put our expertise to good use,” said Lin.

    Their early research, posted online in September 2020, demonstrated that a hepatitis C drug, boceprevir, slotted reasonably well into the coronavirus protease site. Other scientists built off those findings, including at the pharmaceutical company Pfizer, which ultimately created Paxlovid and received regulatory approval for its use in December 2021. “We knew then that we were on the right track,” said Lin, “and we were motivated to keep going and make an even more effective drug.”

    The Lin lab pooled its collective chemical knowledge to design improvements to their iterative boceprevir-based compounds. Much of the work involved modifying the compound on the atomic scale in intricately detailed computer models to fit more snugly in the coronavirus protease active site.

    “Basically, you put your drug in the active site and you look for gaps where it doesn’t tightly fit. Then you fill those gaps,” said Lin.

    The Stanford researchers approached this challenge in a rational way by adding different configurations of atoms of carbon, nitrogen, and oxygen to the compounds as permitted by the laws of biochemistry.

    “There’s a lot of creativity and intuition involved because everyone is working with the same three atoms, but there are essentially infinite ways to arrange them,” said Lin. “Making these modifications, it’s like playing atomic Tetris.”

    The resulting compounds were then tested against actual coronavirus particles at the Stanford In Vitro Biosafety Level 3 Service Center. After multiple rounds of honing, Lin’s team arrived at the compound designated ML2006a4.

    A promising drug candidate

    In studies with SARS-CoV-2-infected mice, ML2006a4 worked as well as Paxlovid in promoting survival, while offering better protection of the rodents’ lungs and lowering overall virus load in the body.

    The researchers attribute this success to ML2006a4’s extremely refined fit inside coronavirus protease, where the compound boasted a 20-fold higher binding affinity than Paxlovid. That better fit equates to stronger chemical bonds, meaning the drug can stay bound to the protease for a longer time. In this temporal regard, ML2006a4 indeed proved quite sticky: The inhibitor remained attached for approximately 330 minutes, or greater than five hours, whereas the corresponding Paxlovid inhibitor typically fell off its target in just about two minutes.

    From a medication perspective, such staying power translates to spaced-out, smaller doses that can still prevent disease from worsening while giving the immune system a chance to kill off the invaders. “The long-lived drug-enzyme complex helps ensure that the virus doesn’t escape and replicate before your next medication dose,” said Lin.

    In this way, ML2006a4 offers other advantages compared to Paxlovid. Technically, Paxlovid is two drugs packaged together: nirmatrelvir, the actual protease inhibitor, and ritonavir, a drug that prevents the liver from quickly breaking down nirmatrelvir, boosting nirmatrelvir’s performance. Yet the slowing of the liver’s metabolism by ritonavir means that other drugs can toxically build up, forcing patients to take the risk of temporarily stopping their normal medications.

    According to Lin, an oral pill based on ML2006a4 might not require ritonavir to prop up drug levels enough between typical 12-hour administrations to effectively keep coronavirus in check, but “this would need to be tested to make sure,” said Lin. “We also continue to make improved versions of ML2006a4 with better potency and duration of activity,” he added.

    For the promising compounds to move forward, Lin and colleagues are seeking additional investment. So far, their funding has mostly consisted of small grants geared toward early-stage drug discovery. The group now feels their compounds are ready for expanded preclinical testing with an eye toward clinical trials in human patients.

    “We’re very excited how far we’ve come and how successful our drug discovery has been on a shoestring budget,” said Lin. “We hope to see this promising compound developed further to stay ready for what SARS-CoV-2 throws at us next.”

    Source:

    Journal reference:

    Park, T., et al. (2024) Single-mode squeezed-light generation and tomography with an integrated optical parametric oscillator. Science Advances. doi.org/10.1126/sciadv.adl1814.

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  • Anti-inflammatory gene variant shields men under 75 from severe COVID-19

    Anti-inflammatory gene variant shields men under 75 from severe COVID-19

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    A certain variant of a key anti-inflammatory gene protects men under age 75 from severe illness and death when hospitalized from COVID-19, a genetic analysis of their blood shows.

    According to the study authors, the protective gene in question, an interleukin-1 receptor antagonist (IL1RN) variant, appears to tamp down inflammation. Inflammation is the body’s normal reaction to infection, but when unchecked, inflammation can go too far and damage tissues as part of many diseases, including in severe cases of infection with the pandemic virus SARS-CoV-2.

    Published as a “major article” in The Journal of Infectious Diseases online March 13, the study showed that 124 men between the ages of 19 and 74 who possessed the IL1RN variant, called rs419598, were less likely to become severely ill after hospitalization for COVID-19 and 80 percent less likely to die from the disease.

    IL1RN is expressed naturally in the body. Different types of interleukin genes are known to dial inflammation up or down in the context of arthritis, and researchers say the results of the current study suggest that a similar dynamic influences the interleukin-1-related inflammation seen in patients with COVID-19.

    The findings, from researchers at NYU Grossman School of Medicine, stand out because historically more men than women are known to die from COVID-19, and the IL1RN rs419598 variant appears to selectively protect only men up to age 74, but not beyond that, as age-related chronic illnesses unfold.

    The research team used sequencing technologies for the study to determine the presence of specific genes or variations in the letter code that makes up genes in blood samples from 2,589 men and women hospitalized for COVID-19 at NYU Langone’s Tisch Hospital in Manhattan from March 2020 to March 2021.

    More than half of the men and women in the study were older than age 60 and had obesity, factors that are known to increase the risk of death from the viral infection. Overall, more men than women (240 men, at 60.5 percent, and 157 women, at 39.5 percent) died from their disease, with women 20 percent less likely to die than men.

    Our study results show that among hospitalized patients, while women are still overall less likely than men to die from COVID-19, those men age 74 and younger who possess the IL1RN gene variant rs419598 are much less likely to suffer the severe inflammation tied to SARS-CoV-2 infection and less likely to die from the disease.”


    Mukundan G. Attur, PhD., study co-lead investigator and molecular biologist

    Dr. Attur is an associate professor in the Department of Medicine at NYU Langone Health.

    Among the study’s other findings was that average blood levels of the anti-inflammatory protein IL-1Ra, coded by IL1RN, were 14 times higher in 181 hospitalized men than in healthy male study controls from the general population, and 10 times as high in 178 hospitalized women than in healthy females. However, researchers say the increased levels of IL-1Ra in women did not result in any statistically significant reductions in death.

    Our analysis offers substantial evidence of the biological link between the severe inflammation seen in SARS-CoV-2 and that which occurs in rheumatoid arthritis.”


    Steven Abramson, MD, study senior investigator, the Frederick H. King Professor of Internal Medicine at NYU Langone

    Dr. Abramson, a rheumatologist who also serves as chair of the Department of Medicine and chief academic officer at NYU Langone, says previous research has shown that such rheumatoid inflammation is lower in people who possessed one of the three IL1RN variants analyzed in the study.

    More importantly, Dr. Abramson says, the new research suggests that restraining the interleukin-1 biological pathway, which is in part tamped down by the anti-inflammatory protein IL-1Ra, could help prevent the severe inflammation seen in SARS-CoV-2 infection. Further research, he says, is warranted into whether IL1-inhibiting therapies, such as the IL1 receptor antagonists anakinra, canakinumab, and rilonacept, are effective against COVID-19 infection.

    Dr. Abramson already has plans to investigate if the IL-1 pathway plays a role in long COVID, when people experience new or lingering symptoms, such as fatigue and brain fog, months after recuperating from their initial infection.

    Dr. Abramson points out that the new study adds to the growing scientific evidence about the biological factors that contribute to the differences between the sexes seen in deaths from COVID-19, which are known to vary widely across the United States.

    Funding support for this study was provided by National Institutes of Health grants P30CA016087 and R21AR078466.

    Besides Dr. Abramson and Dr. Attur, other NYU Langone researchers involved in this study are co-lead investigators Christopher M. Petrilli, MD, and Samrachana Adhikari, PhD, and study co-investigators Eduardo Iturrate, MD; Xiyue Li, MS; Stephanie Tuminello, MPH; Nan Hu, MS; Aravinda Chakravarti, PhD; and David B. Beck, MD, PhD.

    Source:

    Journal reference:

    Attur, M., et al. (2024) Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19. The Journal of Infectious Diseases. doi.org/10.1093/infdis/jiae031.

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  • Research highlights the need for continued surveillance of emerging SARS-CoV-2 variants and vaccines

    Research highlights the need for continued surveillance of emerging SARS-CoV-2 variants and vaccines

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    Researchers at the Francis Crick Institute and the National Institute for Health and Care Research Biomedical Research Centre at UCLH have highlighted the importance of continued surveillance of emerging SARS-CoV-2 variants and vaccine performance as the virus continues to evolve.

    Published today as a research letter in The Lancet, their study compared the newer monovalent COVID vaccine, which specifically targets the XBB variant of Omicron (as recommended by the World Health Organisation), with older bivalent vaccines containing a mix of an Omicron variant and the original strain of COVID-19, which the UK deployed in Autumn 2023 before turning to monovalent vaccines1. 

    The researchers found that both vaccines generated neutralizing antibodies against the most recent strain of Omicron, BA.2.86. However, the new monovalent vaccine generated higher levels of antibodies against a range of other Omicron variants.

    The team collected blood and nasal mucosal samples both before and after a fifth dose vaccination from 71 participants of the Legacy study, a research collaboration between the Crick and the NIHR University College London Hospitals Biomedical Research Centre. They compared the antibody levels before and after vaccination.

    All 36 participants who received the bivalent vaccine and 17 who received the monovalent vaccine had boosted levels of antibodies against all variants tested, including the newest strain BA.2.86, which caused a wave of infection this winter. But those with the newer monovalent vaccine had 3.5x higher levels of antibodies against the XBB and BQ.1.1 strains after their booster vaccination.

    Since the Omicron virus is highly transmissible and the virus replicates in the nose and throat, the researchers tested the levels of antibodies in the participants’ nasal cavity.

    They found that the monovalent vaccine increased their ability to produce mucosal antibodies against most of the tested variants, whereas the bivalent vaccine didn’t provide a significant boost.

    Neither vaccine increased neutralizing antibody levels in the nasal cavity against the newest variant, BA.2.86, suggesting that current vaccines may be less likely to stop transmission or prevent asymptomatic or mild illness, while still protecting against severe disease.

    This highlights the importance of careful vaccine updates and continuing to complement a vaccination program with the development of antibody drugs that work against all variants, as some more vulnerable people don’t respond well to vaccines.

    The UK’s strategy to deploy stocks of older vaccines paid off last year, as both vaccines provided equal protection against the newest strain. However, ongoing monitoring is needed, as the virus is continuing to evolve, so vaccine-induced antibodies might not work so well in the future. In the long run, vaccines that are effective against all new variants and can block COVID-19 being transmitted from person to person are needed.”


    Emma Wall, Senior Clinical Research Fellow at the Crick and Consultant in Infectious Diseases at UCLH

    David LV Bauer, Group Leader of the RNA Virus Replication Laboratory at the Crick, said: “The situation this winter could have been different if the newly emerged BA.2.86 and JN.1 variants were substantially distinct from older Omicron variants, but fortunately this wasn’t the case.

    “Most new variants arise quicker than most clinical trials can produce data. But laboratory analysis can provide a detailed picture very quickly. Continued surveillance will help us stay on top of viral evolution.”

    Source:

    The Francis Crick Institute

    Journal reference:

    Shawe-Taylor, M., et al. (2024) Divergent performance of vaccines in the UK autumn 2023 COVID-19 booster campaign. The Lancet. doi.org/10.1016/S0140-6736(24)00316-7.

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