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Tag: SARS-CoV-2

  • Molnupiravir influences SARS-CoV-2 evolution in immunocompromised patients

    Molnupiravir influences SARS-CoV-2 evolution in immunocompromised patients

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    In a recent study published in The Lancet Microbe, researchers investigated the effects of molnupiravir on the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunocompromised patients.

    Persistent SARS-CoV-2 infection in individuals who are immunocompromised offers genomic variation and has been linked to viral evolution. Antiviral therapy is recommended in immunocompromised patients with acute infection to prevent severe disease. Molnupiravir is the only alternative when first-line therapies (remdesivir and ritonavir-boosted nirmatrelvir) are not feasible, available, or appropriate.

    Study: Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study. Image Credit: creativeneko / ShutterstockStudy: Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study. Image Credit: creativeneko / Shutterstock

    Molnupiravir has been used worldwide in hospital and community settings as well as for immunocompromised patients. Nevertheless, it has been ineffective at reducing coronavirus disease 2019 (COVID-19) hospitalization and mortality rates in high-risk groups, and consequently, it has been designated a third-line therapeutic option. The drug triggers mutagenesis by introducing β-D-N4-hydroxycytidine, the prodrug, into the viral ribonucleic acid (RNA).

    The viral RNA polymerase uses this modified RNA as the template, and an error catastrophe occurs, inhibiting the viral replication. During RNA synthesis, molnupiravir behaves like a cytosine (C) and pairs with guanine (G); however, once incorporated, it transforms into a tautomer analogous to uracil (U), leading to G-to-A mutations in the subsequent round of replication. Likewise, it can induce C-to-U (or -thymine [T]) mutations during the synthesis of the positive-sense genome.

    Reverse T-to-C and A-to-G mutations are also possible but are less frequent. G-to-A mutations indicate molnupiravir treatment; distinctive mutational profiles with extensive G-to-A mutations have been found in global sequences and phylogenetic trees. This is linked to the use of molnupiravir as countries showing long G-to-A branches had increased use of the drug. Contrastingly, countries with infrequent G-to-A branches have not authorized molnupiravir.

    About the study

    In the present study, researchers analyzed the sequencing data from immunocompromised patients with SARS-CoV-2 infection to assess the effects of molnupiravir on viral evolution. The team sequenced around 100 genomes weekly from December 2021 to September 2022, specifically focusing on samples from reinfections, hospitalized patients, overseas travelers, and suspected residential care- and healthcare-related infections.

    Immunocompromised patients with protracted infection were also covered. The team selected nine patients with the same variant with multiple samples (from distinct time points). Four patients (controls) were tested before molnupiravir was available, and five were sampled pre- and post-molnupiravir treatment. All molnupiravir recipients and two controls were immunocompromised. Seven patients received ≥ two vaccine doses, and two were non-vaccinated.

    Patients’ prior infection status was unknown. Patients infected with similar variants and high-quality genomes were selected for group comparisons across time points. Accumulated mutations were compared between groups. The ultrafast sample placement on existing trees (UShER) pipeline and the University of California Santa Cruz genome viewer were leveraged to compare variants from patients with global reference sequences and visualize the locations of mutations.

    Findings

    The team noted that SARS-CoV-2 genomes acquired an average of 30 new low/mid frequency variants by 10 days post-molnupiravir treatment. These changes in viral diversity were not observed in patients who did not receive molnupiravir. On average, 3.3 mutations were acquired per day in the molnupiravir group.

    The probability of observing no mutations among controls during the study period was extremely low. Non-synonymous mutations were common in the spike protein, and subsequent samples indicated that some mutations were fixed. In one patient, 10 non-synonymous mutations were fixed by 35 days post-treatment.

    Accrued mutations were scattered throughout the genome, including those not detected in global Omicron genomes. Mutations acquired in the spike protein clustered at two locations, and their functional relevance was unclear. No known drug-resistance mutations were observed; however, non-synonymous mutations in the open reading frame 1b (ORF1b) were noted.

    The UShER analysis revealed potentially rare/novel mutations in the sequences following treatment. Some samples could not be placed on the global SARS-CoV-2 phylogeny as many mutations were phylogenetically distinct. Mutational profiles post-treatment revealed dominant G-to-A and C-to-T mutations, representing 70% of mutations, which persisted up to 44 days post-treatment.

    Conclusions

    In sum, the findings showed that molnupiravir use in immunocompromised patients modified the patterns of viral evolution, with effects lasting beyond the five-day treatment period. This highlights the risks of treating this subgroup of patients with an error-generating antiviral. The evolution rate in molnupiravir recipients exceeded that observed in non-recipients in this study and globally. Overall, the researchers provided more evidence of the causal link between molnupiravir and the altered mutational landscape of SARS-CoV-2.

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  • Inflammatory responses fuel cardiovascular complications

    Inflammatory responses fuel cardiovascular complications

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    In a recent study published in the journal Circulation, researchers investigate the inflammatory response to acute respiratory distress syndrome (ARDS) within the heart.

    Study: Virus-Induced Acute Respiratory Distress Syndrome Causes Cardiomyopathy Through Eliciting Inflammatory Responses in the Heart. Image Credit: Kateryna Kon / ShutterstockStudy: Virus-Induced Acute Respiratory Distress Syndrome Causes Cardiomyopathy Through Eliciting Inflammatory Responses in the Heart. Image Credit: Kateryna Kon / Shutterstock

    The link between respiratory viral infections and CVD

    Seasonal viral infections can range in severity from mild flu-like symptoms to potentially lethal ARDS. For example, despite being primarily a respiratory tract infection, coronavirus disease of 2019 (COVID-19) can lead to ARDS and other severe cardiovascular disease outcomes with high mortality rates.

    Circulating immune cells may respond to COVID-19 by upregulating cytokine release, which can lead to myocardial injury. Cardiac macrophages, immune cells responsible for the myocardial inflammatory response, are increasingly being investigated for their role in ARDS. Recent evidence indicates that macrophage expansion, which can be accompanied by changes in the population size and relative abundances of various cardiac macrophages, is a characteristic feature of ARDS.

    The main two types of cardiac macrophages include C-C chemokine receptor type 2 negative (CCR2–) and CCR2+ macrophages. Further research is needed to determine the viral-induced contributions of these macrophages to adverse cardiac outcomes.

    These data would allow clinicians to make informed intervention decisions and elucidate whether these outcomes are COVID-19-induced or if observed inflammation is a systemic immune response to viral infection. Furthermore, this information could support the development of future therapies to prevent cardiovascular disease (CVD) following recovery from COVID-19.

    About the study

    In the present study, researchers investigate the role of viral- and non-viral-induced ARDS-associated immune signals in altering cardiac macrophage populations, thereby impacting CVD parameters, including systemic inflammation.

    This study was conducted at Massachusetts General Hospital and involved 33 control samples obtained from patients who died between September and December 2019, prior to the onset of COVID-19, as well as 21 samples obtained between May and July 2020 from patients who died from COVID-19-associated complications. Samples consisted of autopsy tissue excised from the left ventricular or septal region.

    Simultaneously, in vivo studies involved a daily intratracheal administration of an ARDS cocktail of immunostimulatory agents to mice, which included resiquimod, imiquimod, lipopolysaccharide (LPS), and angiotensin-converting enzyme 2 (ACE2) inhibitor MLN-4760. This model allowed the researchers to reproduce clinical ARDS features in mice without the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

    Patient data included results obtained from electrocardiogram (ECG), echocardiography, lung computed tomography (CT) scan, blood gas analyses, body temperature evaluation, bronchoalveolar lavage fluid (BALF) characterization, blood pressure measurements, and flow cytometry. Both human and murine autopsy samples were processed using ribonucleic acid (RNA) isolation, real-time polymerase chain reaction (PCR) assay, and enzyme-linked immunosorbent assays (ELISAs) for protein and gene expression determinations.

    Similar immune responses in non-viral- and SARS-CoV-2-associated ARDS

    In the absence of viral infection, mice treated with the ARDS cocktail exhibited significant weight loss over the five-day cocktail treatment period. This was accompanied by hypothermia, a common feature of both ARDS and septic shock, as well as a mortality rate of over 40% by day five.

    Mice with ARDS exhibited bilateral opacities and immune cell infiltrations within their lungs, as well as reduced blood oxygenation. Furthermore, increased D-dimer, neutrophil, and monocyte levels were observed, as well as reduced blood pressure and lower heart rates in ARDS mice. Other inflammatory pathways that were activated in ARDS mice included increased levels of interleukin 6 (IL-6), IL-1ß, tumor-necrosis factor α (TNF-α), and interferon y (IFN-y), all of which are also associated with SARS-CoV-2 infection.

    In both non-infected ARDS and SARS-CoV-2-infected mice, an increased infiltration of interstitial macrophages and reduced levels of alveolar macrophages were observed. Although both mouse models exhibited increased levels of cardiac macrophages, this immune response was more pronounced in infected mice. Nevertheless, both models’ subsets of cardiac macrophages were altered to similar levels.

    Upon comparison of control and COVID-19 patient myocardium samples, SARS-CoV-2 infection recruited a more significant number of CCR2+ CD68+ macrophages, thus indicating that a robust immune response is elicited after severe infection compared to other life-threatening diseases.

    “Our findings indicate that systemic and myocardial inflammatory signals elicited by virally induced ARDS may contribute to the cardiovascular complications and high mortality rates of this condition. In addition, our study confirms previous reports that SARS-CoV-2 infection increases overall macrophage numbers in hearts.”

    The cardiac benefits of TNF-α immune therapy

    TNF-α neutralizing antibodies were also administered to mice to evaluate their effects on immune activation during ARDS. To this end, TNF-α immune therapy reduced weight loss, improved body temperature, increased blood oxygenation, and led to better survival rates. Histological analysis indicated that ARDS mice receiving anti-TNF-α therapy exhibited reduced macrophages, Cxcl2, IL-1ß, and IL-6 expression within the lungs.

    TNF-α therapy also improved systolic dysfunction, cardiomyocyte apoptosis, and monocyte infiltration in ARDS mice. Total cardiac macrophage counts and reduced expression of IL-1ß, IL-6, and TNF-α within the myocardium were also observed, thus demonstrating the anti-inflammatory benefits associated with TNF-α immune therapy in the lungs and hearts of mice with ARDS.

    Conclusions

    The study findings demonstrate that SARS-CoV-2 infection leads to significant alterations in cardiac macrophage subset levels, particularly increased levels of CCR2+ macrophages, in both mice and humans. Even in the absence of SARS-CoV-2 or another virus, the immune response to ARDS-like injury is capable of inducing significant alterations in heart macrophage levels, which may increase the risk of cardiovascular complications and mortality associated with ARDS.

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  • Antibiotics can effectively target gut bacteria that harbor COVID-19 virus, study shows

    Antibiotics can effectively target gut bacteria that harbor COVID-19 virus, study shows

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    New research indicates that antibiotics can effectively target bacteria in the gut that harbor the virus that causes COVID-19 and produce toxin-like peptides that contribute to COVID-19-related symptoms. In the study, which involved 211 participants and was published in the Journal of Medical Virology, individuals who received early antibiotic treatment after having COVID-19 recovered more quickly than those who did not receive antibiotics.

    The authors had already evaluated the efficacy of certain antibiotics in SARS-CoV-2-infected bacterial cultures in vitro, and this new study demonstrates promising results with the use of the combination of 2 antibiotics (amoxicillin and rifaximin) within the first 3 days.

    Furthermore, a significant number of patients who received antibiotics within the first 3 days and for a duration of 7 days during the acute phase of COVID-19 did not develop long COVID.

    Our findings suggest that antibiotics should be considered in acute infection and Long COVID. The study also lays the foundation for additional vaccine strategies.”

    Marina Piscopo, PhD, co-corresponding author of the University of Naples Federico, Italy

    Source:

    Journal reference:

    Brogna, C., et al. (2024) A retrospective cohort study on early antibiotic use in vaccinated and unvaccinated COVID-19 patients. Journal of Medical Virology. doi.org/10.1002/jmv.29507.

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  • Google AI could soon use a person’s cough to diagnose disease

    Google AI could soon use a person’s cough to diagnose disease

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    Person coughing into their elbow while in bed.

    The field of audiomics combines artificial intelligence tools with human sounds, such as a coughs, to evaluate health.Credit: Getty

    A team led by Google scientists has developed a machine-learning tool that can detect and monitor health conditions by evaluating noises such as coughing and breathing. The artificial intelligence (AI) system1, trained on millions of audio clips of human sounds, might one day be used by physicians to diagnose diseases including COVID-19 and tuberculosis and to assess how well a person’s lungs are functioning.

    AI detects eye disease and risk of Parkinson’s from retinal images

    This is not the first time a research group has explored using sound as a biomarker for disease. The concept gained traction during the COVID-19 pandemic, when scientists discovered that it was possible to detect the respiratory disease through a person’s cough2.

    What’s new about the Google system — called Health Acoustic Representations (HeAR) — is the massive data set that it was trained on, and the fact that it can be fine-tuned to perform multiple tasks.

    The researchers, who reported the tool earlier this month in a preprint1 that has not yet been peer reviewed, say it’s too early to tell whether HeAR will become a commercial product. For now, the plan is to give interested researchers access to the model so that they can use it in their own investigations. “Our goal as part of Google Research is to spur innovation in this nascent field,” says Sujay Kakarmath, a product manager at Google in New York City who worked on the project.

    How to train your model

    Most AI tools being developed in this space are trained on audio recordings — for example, of coughs — that are paired with health information about the person who made the sounds. For example, the clips might be labelled to indicate that the person had bronchitis at the time of the recording. The tool comes to associate features of the sounds with the data label, in a training process called supervised learning.

    Google AI has better bedside manner than human doctors — and makes better diagnoses

    “In medicine, traditionally, we have been using a lot of supervised learning, which is great because you have a clinical validation,” says Yael Bensoussan, a laryngologist at the University of South Florida in Tampa. “The downside is that it really limits the data sets that you can use, because there is a lack of annotated data sets out there.”

    Instead, the Google researchers used self-supervised learning, which relies on unlabelled data. Through an automated process, they extracted more than 300 million short sound clips of coughing, breathing, throat clearing and other human sounds from publicly available YouTube videos.

    Each clip was converted into a visual representation of sound called a spectrogram. Then the researchers blocked segments of the spectrograms to help the model learn to predict the missing portions. This is similar to how the large language model that underlies chatbot ChatGPT was taught to predict the next word in a sentence after being trained on myriad examples of human text. Using this method, the researchers created what they call a foundation model, which they say can be adapted for many tasks.

    An efficient learner

    In the case of HeAR, the Google team adapted it to detect COVID-19, tuberculosis and characteristics such as whether a person smokes. Because the model was trained on such a broad range of human sounds, to fine-tune it, the researchers only had to feed it very limited data sets labelled with these diseases and characteristics.

    On a scale where 0.5 represents a model that performs no better than a random prediction and 1 represents a model that makes an accurate prediction each time, HeAR scored 0.645 and 0.710 for COVID-19 detection, depending on which data set it was tested on — a better performance than existing models trained on speech data or general audio. For tuberculosis, the score was 0.739.

    An AI revolution is brewing in medicine. What will it look like?

    The fact that the original training data were so diverse — with varying sound quality and human sources — also means that the results are generalizable, Kakarmath says.

    Ali Imran, an engineer at the University of Oklahoma in Tulsa, says that the sheer volume of data used by Google lends significance to the research. “It gives us the confidence that this is a reliable tool,” he says.

    Imran leads the development of an app named AI4COVID-19, which has shown promise at distinguishing COVID-19 coughs from other types of cough3. His team plans to apply for approval from the US Food and Drug Administration (FDA) so that the app can eventually move to market; he is currently seeking funding to conduct the necessary clinical trials. So far, no FDA-approved tool provides diagnosis through sounds.

    The field of health acoustics, or ‘audiomics’, is promising, Bensoussan says. “Acoustic science has existed for decades. What’s different is that now, with AI and machine learning, we have the means to collect and analyse a lot of data at the same time.” She co-leads a research consortium focused on exploring voice as a biomarker to track health.

    “There’s an immense potential not only for diagnosis, but also for screening” and monitoring, she says. “We can’t repeat scans or biopsies every week. So that’s why voice becomes a really important biomarker for disease monitoring,” she adds. “It’s not invasive, and it’s low resource.”

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  • 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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  • COVID’s toll on the brain: new clues emerge

    COVID’s toll on the brain: new clues emerge

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    Nature, Published online: 20 March 2024; doi:10.1038/d41586-024-00828-9

    A leaky blood–brain barrier and inflammation might account for some of the cognitive symptoms of COVID-19.

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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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