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Tag: Respiratory

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

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

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

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

    Background

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

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

    About the study

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

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

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

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

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

    Results

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

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

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

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

    Conclusions

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

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

    Journal reference:

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

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

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

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

    Background

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

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

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

    About the study

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

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

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

    Results and discussion

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

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

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

    Conclusion

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

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  • New study pinpoints key markers for Long COVID diagnosis

    New study pinpoints key markers for Long COVID diagnosis

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

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

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

    COVID-19 and the need for Long COVID diagnosis

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

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

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

    About the study

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

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

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

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

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

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

    Study findings

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

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

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

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

    Conclusions

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

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

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

    Journal reference:

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


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

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

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

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

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

    Background

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

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

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

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

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

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

    What did the study show?

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

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

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

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

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

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

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

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

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

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

    What are the implications?

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

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

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

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

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  • Smoking, infection, and BMI found to significantly sway immune response, study shows

    Smoking, infection, and BMI found to significantly sway immune response, study shows

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    In a recent study published in the journal Nature, researchers explored the factors influencing cytokine release, a critical component of the host immunological response.

    The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emphasized the wide variation in immunological responses between populations, with age, sex, and genetic variables all playing vital roles. However, therapy and vaccine development often disregard immunological diversity. The Milieu Intérieur research project has contributed to understanding immune homeostasis by quantitatively evaluating the impacts of age, gender, cellular composition, and genetics on immune-related gene transcript levels and those of age, gender, smoking, and cytomegalovirus (CMV) infections on leukocyte distribution in blood. Further study might help us better understand the elements that influence immune responses and how they affect clinical outcomes.

    Study: Smoking changes adaptive immunity with persistent effects. Image Credit: NeydtStock / ShutterstockStudy: Smoking changes adaptive immunity with persistent effects. Image Credit: NeydtStock / Shutterstock

    About the study

    In the present study, researchers investigated environmental variables associated with cytokine responsiveness to immunological activation.

    The team measured the levels of several cytokines [C‐X‐C motif chemokine ligand 5 (CXCL5), colony-stimulating factor 2 (CSF2), interferon-gamma (IFNγ), interleukin-1 beta (IL-1β), IL-2, 6, 8, 10, 12p70, 13, 17, 23, and tumor necrosis factor (TNF)] after 22 hours of whole-blood stimulations with 11 immunological agonists for 1,000 Milieu Intérieur project donors and in an unstimulated (control) condition. They categorized the stimulations as microbial, viral, T-lymphocyte activated, and cytokines.

    Heat maps and principal component analyses (PCA) of 13 cytokine molecules investigated in 12 immunological stimulations revealed the individual cytokines generated by every independent condition. The team performed hierarchical clustering evaluations of log mean variations in cytokine levels to identify groups corresponding to stimulation types.

    The researchers compiled 136 environmental, socio-demographic, nutritional, and clinical variables from the digital case report forms and tested for their relationships with cytokines induced in every stimulation using likelihood ratio tests (LRTs) with age, experimental batch, and gender as covariates. They also investigated human leukocyte antigen (HLA) as a predictor of immune response variability, particularly in antigen-specific responses. The team investigated whether smoking-cytokine correlations continued when particular subsets of circulating immune cells were included in their models, as these cells are related to cytokine elevations. They evaluated the biological impact of smoking on cytokine production, calculating the effect sizes for the smoking variables in the linear models and assessing the influence of 326 soluble proteins in sera obtained from 400 donors.

    The researchers investigated whether epigenetic pathways contribute to the impact of smoking on adaptive immune responses. They analyzed deoxyribonucleic acid (DNA) methylation at more than 850,000 CpG sites and investigated whether the levels may explain the association between smoking and cytokine levels following SEB stimulation. The study was especially well-suited to identifying response protein quantitative trait loci (pQTLs) since it tested 5,699,237 high-quality imputed single nucleotide polymorphisms (SNPs) for relationships with the cytokines elicited by each stimulation.

    Results

    The team identified smoking, CMV latent infection, and body mass index (BMI) as the most significant drivers of cytokine response variability. Smoking impacts innate and adaptive immune responses, with the influence on innate responses diminishing after quitting and associated with serum carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) levels. However, the impact on adaptive responses lasts long after smoking cessation and is associated with epigenetic memory.

    The study highlighted eleven factors related to one or more cytokines in the immune stimulations, with BMI being the most prevalent. Smoking-related factors were related to interleukin-2 and interleukin-13 (adaptive immunity) in Staphylococcus aureus enterotoxin B superantigen (SEB), anti-cluster of differentiation 3 (anti-CD3) and anti-CD28 immune stimulations, and CXCL5 following Escherichia coli infections or innate immunological stimulations. The findings indicate that smoking causes inflammation and reduces immunity against bacterial infections.

    Cytomegalovirus latent infection was associated with TNF, CSF2, and IFNγ cytokines secreted by adaptive immune cells. BMI-related factors were related to CXCL5 following Bacillus Calmette-Guérin (BCG) immune stimulation, and interleukin-2 following SEB stimulation demonstrated obesity dysregulation. The team found no significant association between major histocompatibility complex (MH) class II, DQ beta 1, and HLA.DBQ1.1P, and IL-6 in the control condition.

    The study found 2,416 CpG locations related to smoking in the Milieu Intérieur sample, with 129 significantly associated with IL-2 in SEB stimulation. However, 11 CpGs abolished the relationship between smoking and IL-2 and IL-13. Current smokers had lower DNA methylation than non-smokers, but former smokers had an intermediate methylation level. The number of years smoked, total cigarettes smoked, and IL-2 levels in SEB stimulation were adversely linked with DNA methylation, although the number of years after smoking typically correlated positively.

    Overall, the study findings identified three novel factors, i.e., smoking status, CMV latent infection, and BMI, associated with variability in cytokine secretion following immunological stimulation. These characteristics may have clinical consequences for the risk of contracting infections, cancer, or autoimmune diseases. Smokers have a heightened inflammatory response after bacterial activation, which promptly decreases after quitting. However, the impacts on adaptive immunity last for years after stopping. The link between smoking and long-lived B and T cell subsets and DNA methylation offers a potential for long-term consequences in the adaptive response.

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  • Fluid-filled lung sac found to be the hub for virus-eating cells

    Fluid-filled lung sac found to be the hub for virus-eating cells

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    Scientists have long thought of the fluid-filled sac around our lungs merely as a cushion from external damage. Turns out, it also houses potent virus-eating cells that rush into the lungs during flu infections.

    Not to be confused with phages, which are viruses that infect bacteria, these cells are macrophages, immune cells produced in the body. 

    “The name macrophage means ‘big eater.’ They gobble up bacteria, viruses, cancer cells, and dying cells. Really, anything that looks foreign, they take it up and destroy it,” said UC Riverside virologist Juliet Morrison, who led the discovery team. “We were surprised to find them in the lungs because nobody has seen this before, that these cells go into the lung when there’s an infection.”

    A paper published in the Proceedings of the National Academy of Sciences details how during an influenza infection, macrophages leave the exterior cavity and cross into the lungs where they decrease inflammation and reduce levels of disease. 

    This study shows it’s not just what happens in the lung that matters, but also what’s outside of the lung. Cell types not normally connected to the lung can have outsized impacts on lung disease and health.”


    Juliet Morrison, UC Riverside virologist

    There are three main cavities in the body: one around the heart, the abdominal cavity, and the pleural cavity surrounding the lungs. “Because it contains fluid, it prevents the lungs from collapsing. However, people have not thought much about the pleural cavity being a whole organ within itself. This research may change that perception,” Morrison said.

    Initially, the researchers set out to understand the more general question of what types of cells are present in the lungs during flu infections. They took existing data on lung-related genes from studies of mice that either died from the flu or survived. They then mined the data using an algorithm to predict cell types that change in the lungs during infections. 

    “We took big data and broke it down to assign which potential immune cells are in the lung tissues. That’s where I got a hint that maybe we had a previously unknown external source of cells in the lung,” Morrison said. 

    Next, using a laser-based technique, the team tracked macrophages going into the lungs of mice, and observed what happened if they took these cells out of the equation. “When you take them out of the mouse you see more disease and more lung inflammation,” Morrison said. 

    Morrison says she hopes this study will encourage other scientists to reevaluate data sets from older studies. “Our approach was to take information already out there and put it to new use, and we were able to see something new,” she said. 

    Moving forward, the research team is hoping to determine which proteins “tell” the macrophages to move into the lungs. Once the protein signals have been identified, it may be possible to create drugs that boost either the number of macrophages, or their activity.

    The strategy of boosting human defenses to infection, rather than developing another antiviral, could offer people a flu treatment that would be more effective for much longer. Morrison became interested in host therapeutics because antibiotic and antiviral resistance to drugs is a growing problem.

    This problem occurs when germs like bacteria and fungi develop the ability to defeat the drugs designed to kill them. Misuse and overuse of the drugs is accelerating the problem. According to the Centers for Disease Control and Prevention, more than 2.8 million drug-resistant infections occur each year in the U.S., and more than 35,000 people die as a result. 

    “If we can boost what resolves infection in us, we probably have a better shot. We’re less likely to have resistance. The immune system is so complicated, but it’s our best bet in the long run to work with what we have rather than chase viruses that continue to escape our therapeutics,” Morrison said. 

    Source:

    University of California – Riverside

    Journal reference:

    Stumpff, J. P., et al. (2023). Pleural macrophages translocate to the lung during infection to promote improved influenza outcomes. PNAS. doi.org/10.1073/pnas.2300474120.

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  • A closer look reveals lasting impacts

    A closer look reveals lasting impacts

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    In a recent study published in the journal Pediatrics, a large team of scientists from the United States (U.S.) reviewed existing studies on post-acute sequelae of coronavirus disease 2019 (COVID-19) (PASC) to understand the long-term impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the pediatric population, including factors such as prevalence, clinical characteristics, risk factors, and underlying mechanisms.

    ​STATE-OF-THE-ART REVIEW – Postacute Sequelae of SARS-CoV-2 in Children. Image Credit: Donkeyworx / Shutterstock

    Background

    The global impact of the COVID-19 pandemic has touched multiple spheres of life, with economic and social consequences apart from the massive effect on the medical and healthcare fields. Studies have shown that the pandemic has disproportionately affected specific racial and socioeconomic groups. Furthermore, a significant portion of the population continues to struggle with persistent and debilitating aftereffects and symptoms of COVID-19, which has now been called PASC or long coronavirus disease (long COVID).

    Estimates indicate that the U.S. had approximately 20% pediatric cases of COVID-19, of which 10%–20% were thought to develop into PASC, which translates to roughly 5.8 million children in the country. The present study summarizes the current understanding of the epidemiology, prevalence, underlying mechanisms, clinical characteristics, and outcomes of PASC in the pediatric population.

    PASC epidemiology

    The review found no consensus on the prevalence of PASC among children, with a 4% to 62% prevalence being reported across studies. The researchers believe that differences in factors such as study design, follow-up durations, diagnostic criteria, and study population are responsible for the wide range of prevalence estimates. Furthermore, the broad symptoms, affecting multiple organ systems, and overlaps with existing comorbidities also make it challenging to diagnose PASC.

    There is also a paucity of studies examining the trajectory of PASC in the pediatric population, with very few studies having examined the progression of the disease beyond a year. Studies found that only 15% of asymptomatic SARS-CoV-2 infections in children progress to PASC, while 45% of the symptomatic infections were found to result in long-lasting sequelae.

    Furthermore, infections with variants before the emergence of Omicron were found to increase the risk of PASC. Increasing age, severity of the infection, higher body weight, chronic underlying medical conditions, and the organ systems affected during the acute SARS-CoV-2 infection were all found to be risk factors for developing PASC.

    While the contribution of environmental and psycho-social factors in the development and manifestation of PASC has not been well investigated, the scientists believe that the escalating food and housing insecurity, disruption of educational and health care resources, and lower family income could have increased the mental and physical health problems in children, lowering immunity, and exacerbating existing illnesses.

    PASC in children

    Based on existing information, the team formulated a conceptual model for PASC in the pediatric population. They defined PASC in children as a heterogeneous group of symptoms occurring after a SARS-CoV-2 infection, consisting of persistent COVID-19 symptoms such as cough, dyspnea, fatigue, headaches, anosmia, ageusia, and chronic pain. Furthermore, exacerbation of existing conditions such as increased cough in children with asthma, deterioration of neurodevelopmental and mental health conditions, and diabetic ketoacidosis in pediatric diabetes cases are also thought to be a part of PASC.

    The review emphasizes the need to give special consideration to understanding the development of PASC in children at a higher risk of SARS-CoV-2 infections due to existing comorbidities and medical conditions. The researchers also discussed the potential development of de-novo post-acute conditions and the onset of autoimmune disorders. Studies have already reported multisystem inflammatory syndrome in children (MIS-C) as being one of the prevalent complications of COVID-19 in children.

    The review also provided a comprehensive summary of the wide range of manifestations and symptoms of PASC, including constitutional symptoms such as persistent fatigue, post-exertional malaise, brain fog or difficulty concentrating, depressive symptoms, and somnolence. The researchers also discussed the respiratory, cardiac, neurological, olfactory, gastrointestinal, mental health, musculoskeletal, dermatological, and inflammatory or hematological manifestations of PASC in detail.

    Furthermore, the study also examined the role of PASC in exacerbating underlying conditions in children, such as asthma, fibromyalgia, and connective tissue disorders, as well as post-infectious conditions such as MIS-C and de-novo conditions such as diabetes, autoimmune disorders, and neurological problems that could potentially develop during PASC.

    Conclusions

    To summarize, the review examined studies investigating the long-term consequences of SARS-CoV-2 infections in children and presented a comprehensive picture of the current understanding of PASC in children. The findings indicate that while the severity and prevalence of COVID-19 in the pediatric population were not as high as in adults, PASC does entail severe and long-lasting consequences, including the development of new autoimmune conditions and diabetes. These results highlight the need to form initiatives to further understand the susceptibility of children with underlying medical conditions to SARS-CoV-2 infections.

    Journal reference:

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  • Drug repurposing study finds lonafarnib effective against RSV

    Drug repurposing study finds lonafarnib effective against RSV

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    In a study published in the journal Nature Communications, researchers screened ReFRAME (short for repurposing, focused rescue, and accelerated Medchem), a drug-repurposing library, for drugs against respiratory syncytial virus (RSV). They identified lonafarnib as a potent inhibitor of RSV fusion protein and investigated its therapeutic potential against an RSV infection.

    Study: Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor. Image Credit: joshimerbin / ShutterstockStudy: Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor. Image Credit: joshimerbin / Shutterstock

    Background

    RSV causes severe lower respiratory tract infections in young children, immunosuppressed individuals, and older adults, with millions of annual hospital admissions and deaths. The recent coronavirus disease 2019 (COVID-19) pandemic and associated interventions have led to altered RSV epidemiology, with a transient suppression and resurgence of RSV circulation, raising concerns about increased infections.

    RSV infection treatment is currently symptomatic. While ribavirin shows in vitro efficacy, it is not very efficacious in patients. Palivizumab provides prophylaxis but is costly, offers only a partial reduction in hospitalization rates, and faces challenges like rapid resistance development. Although nirsevimab was recently approved for RSV prevention in newborns, there remains a dearth of therapeutic options.

    Various antiviral strategies against RSV, including immunoglobulins, are being developed. Repurposing libraries containing licensed drugs or compounds in clinical development serve as repositories with potential for accelerated therapeutic applications. Researchers in the present study screened the ReFRAME library and identified lonafarnib as an RSV fusion protein inhibitor while demonstrating its therapeutic ability.

    About the study

    The library (of 12,000 molecules) was screened using a recombinant RSV subtype A strain GFP (short for green fluorescent protein) reporter virus. Cell viability was determined using an MTT (short for 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The primary hit criteria were RSV infection ≤ 16% and cell viability ≥ 80%. Fourteen molecules met the primary criteria, and 16 additional molecules were selected. Two farnesyl-S-transferase inhibitors, lonafarnib, and tipifarnib, were evaluated and compared for their inhibitory effects on RSV infection. To identify the potential viral target of lonafarnib, passages of the RSV reporter virus were conducted with increasing doses of lonafarnib. The resulting virus populations were sequenced, and mutations were analyzed. The study additionally involved orthogonal infection assays, plaque reduction assays, RSV lentiviral pseudotype assays, and RSV F protein cell-to-cell membrane fusion assays. Surface plasmon resonance and crystallization experiments were conducted to investigate the interaction of lonafarnib with a recombinant RSV subtype A pre-fusion F protein.

    Therapeutic effects of lonafarnib were evaluated by inoculating A549 cells with HRSV-A-GFP, treating with lonafarnib or ribavirin 24 hours post-inoculation, and monitoring virus spread over time. The drug’s effect in a more natural model of RSV infection and cell entry was investigated using the immortalized human basal cell line BCi-NS1.1, which was further differentiated into the pseudostratified ciliated epithelium.

    Six mice were treated with oral lonafarnib or solvent control and infected with an RSV reporter virus. The animals’ weight was monitored, and on day 4, tissues were extracted, and lung RSV copy number was measured.

    A Screening and validation procedure. B HEp-2 cells were infected with rHRSV-A-GFP in presence of 5 µM compound. 48 hours later, infection and cell viability were quantified via GFP and MTT readouts. Dotted lines indicate primary hit criteria and dots represent means of two technical replicates. C HEp-2 cells were infected with HRSV-A-Luc at MOI 0.01 and treated with the indicated compound concentrations. 24 hours later, supernatant was transferred onto new cells for a second round of infection. Luminescence was quantified 24 hours post inoculation of both infection rounds. Cell viability was measured via MTT readout in treated, but uninfected cells. Mean ± SD of three independent experiments. Known RSV inhibitors (F protein: presatovir; N protein: RSV604, IMPDH inhibitors (AVN944, mycophenolic acid), HSP90 inhibitors (radiciol, HSP990). 4-Sulfocalix[6]arene Hydrate (4SC6AH, unknown target). Source data are provided as a Source Data file.A Screening and validation procedure. B HEp-2 cells were infected with rHRSV-A-GFP in presence of 5 µM compound. 48 hours later, infection and cell viability were quantified via GFP and MTT readouts. Dotted lines indicate primary hit criteria and dots represent means of two technical replicates. C HEp-2 cells were infected with HRSV-A-Luc at MOI 0.01 and treated with the indicated compound concentrations. 24 hours later, supernatant was transferred onto new cells for a second round of infection. Luminescence was quantified 24 hours post inoculation of both infection rounds. Cell viability was measured via MTT readout in treated, but uninfected cells. Mean ± SD of three independent experiments. Known RSV inhibitors (F protein: presatovir; N protein: RSV604, IMPDH inhibitors (AVN944, mycophenolic acid), HSP90 inhibitors (radiciol, HSP990). 4-Sulfocalix[6]arene Hydrate (4SC6AH, unknown target). Source data are provided as a Source Data file.

    Results and discussion

    Twenty-one molecules, including lonafarnib, demonstrated antiviral activity against RSV. Lonafarnib is approved for Hutchinson-Gilford progeria syndrome and is in phase III clinical trials for hepatitis delta virus infections. Lonafarnib, but not tipifarnib, demonstrated inhibition of RSV infection, as evidenced by reduced reporter virus activity, plaque reduction, and suppressed syncytia formation in infected cells. Further, lonafarnib, not tipifarnib, was found to interact with the pre-fusion F protein in a binding site that has been previously observed for other fusion inhibitors.

    Lonafarnib-exposed virus populations accumulated two coding mutations (T335I and T400A) within the RSV fusion protein, leading to phenotypic resistance to lonafarnib. Further, lonafarnib was found to inhibit RSV’s entry into the cells by binding to the fusion protein and inhibiting membrane fusion. This inhibition was found to be overcome by resistance mutations in the fusion protein.

    In vitro, combinations of lonafarnib and ribavirin showed minor inhibitory or slightly synergistic activity at selected doses. Lonafarnib treatment post-inoculation in A549 cells restricted the spread of the HRSV GFP virus by 30% as compared to controls. In the BCi-NS1.1 cell culture model, prophylactic lonafarnib treatment from both the apical and basolateral sides dose-dependently inhibited RSV infection, resulting in a 10- to 15-fold reduction in virus load. Therapeutic application of lonafarnib only from the basolateral side also reduced virus load by approximately 50% in a clinical RSV isolate infection.

    In vivo, lonafarnib-treated animals showed a significantly reduced reporter virus signal in the lung and nose compared to controls. On day 4, a dose-dependent decline was observed in viral ribonucleic acid in the lungs of treated mice, and there was a lesser weight loss compared to controls. However, cellular infiltrates were observed in the lungs of lonafarnib-treated mice.

    Conclusion

    In conclusion, the study identified lonafarnib as a potential therapeutic candidate for RSV treatment, highlighting the utility of drug-repurposing studies. The findings demonstrate the promising antiviral activity of lonafarnib in cell culture as well as mice models of RSV infection. Further research is warranted to confirm the findings.

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  • New study finds 4’-fluorouridine effective against avian influenza in vitro and in vivo

    New study finds 4’-fluorouridine effective against avian influenza in vitro and in vivo

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    In a recent study published in the journal PLOS Pathogens, researchers from the United States of America (US) investigated the resistance profile of 4’-fluorouridine (4’-FlU) against an avian influenza pandemic A/CA/07/2009 (H1N1, short for hemagglutinin 1 neuraminidase 1) (CA09).

    Bird flu virus 3d rendering medical illustration surface structure avian influenza
    Study: Influenza A virus resistance to 4’-fluorouridine coincides with viral attenuation in vitro and in vivo. Image Credit: joshimerbin/Shutterstock.com

    They found that the molecule could overcome resistance in six identified escape lineages of the virus in vitro and showed promising results in mice and ferret models.

    Background

    Seasonal influenza viruses significantly impact public health and the economy. Every year, around one billion people worldwide get infected with the virus, and millions require hospitalization and advanced medical care. In interpandemic years, more than 600,000 people die from the disease. When zoonotic influenza viruses spill over into the human population, they can cause large-scale pandemics with even higher case fatalities. Existing influenza vaccines offer moderate protection, but efficacy diminishes in vulnerable populations and during poorly matched or pandemic virus strains.

    Food and Drugs Administration (FDA)-approved antivirals, including adamantes, neuraminidase inhibitors, and baloxavir marboxil, face challenges with low genetic barriers to viral resistance.

    Several antiviral resistance challenges persist, including adamantes’ widespread M2 S31N mutation, neuraminidase inhibitors’ rapid emergence of resistance, baloxavir marboxil’s swift treatment-emergent resistance, and uncertainties surrounding favipiravir’s clinical impact, despite a high resistance barrier.

    In previous studies, 4’-FlU, a broad-spectrum nucleoside analog, was found to be effective against various ribonucleic acid (RNA) viruses, including beta-coronaviruses, respiratory syncytial virus (RSV), and avian influenza viruses, and displayed broad-spectrum activity and a wide therapeutic time window.

    In the present study, researchers explored the therapeutic potential of 4’-FlU via resistance profiling and assessment of the pathogenesis and fitness of resistant recombinants in vitro and in vivo.

    About the study

    The study involved the gradual adaptation of recombinant virus CA09 (recCA09) to 4’-FlU through dose-escalation serial passaging in vitro in six independent lineages. Progeny virus titers were determined at each passage, and whole genome sequencing was conducted on 4’-FlU-experienced virus populations and dimethyl sulfoxide (DMSO)-treated control populations to identify allele-dominant mutations in RNA-dependent RNA polymerase (RdRp).

    The mutations were localized using structural models. The process aimed to assess the development of resistance and understand the genetic changes associated with tolerance to 4’-FlU. Dose-response assays were conducted against recCA09 to determine inhibitory concentrations (EC50 and EC90) of 4’-FIU.

    To assess the resistance profile of 4′-FlU against influenza viruses, in vitro and in vivo models, including cells, mice, and ferrets, were employed. In addition, in silico modeling was used for mechanistic characterization. The virus was intranasally inoculated.

    The viral load was periodically monitored in nasal lavages (of ferrets) and respiratory tissues of mice and ferrets, extracted 4 or 8 days after infection. Statistical analysis involved the use of Student’s t-test and analysis of variance (ANOVA) to compare parameters between the groups.

    Results and discussion

    The EC50 and EC90 of 4’-FIU were found to be 0.14 and 0.24 μM respectively. During the in vitro adaptation of the virus to 4’-FlU six independent escape lineages with distinct mutations in the recCA09 background were generated. A 2–25-fold increase was observed in EC99 concentrations of 4’-FlU against the different lineages, confirming moderate resistance.

    No combinations of mutations conferring moderate resistance to 4’-FlU were found in available complete influenza A virus (IAV) genome sequences. The mutations’ low individual frequency validated 4’-FIU’s efficacy against circulating human and avian IAVs.

    The researchers could identify specific residues crucial for shaping the central cavity of the RdRP as key determinants in moderately reducing polymerase susceptibility to 4’-FlU inhibition. Additionally, they suggest that a substantial genetic barrier may hinder the emergence of more robust resistance.

    Escape was found to arise from individual, additive or synergistic mutations. All the variants showed impaired fitness and attenuation in cell culture and mice models. Although the resistant variants remained pathogenic in the mice, their moderate resistance to 4’-FlU could be overcome pharmacologically in vivo.

    Oral administration of 4’-FlU at either the lowest (2 mg/kg) or elevated (10 mg/kg) dose was found to effectively overcome resistance, as indicated by the survival of the mice. The positive effect of 4’-FIU was also evidenced by reduced clinical signs and lower tissue virus burden.

    Even for variants with the most robust resistance or residual pathogenicity, their transmission is compromised and/or easily controlled by the standard dose of 4’-FlU. In the ferret model, the 4’-FlU-treated variants (representing four adaptation lineages) showed impaired invasion of the lower respiratory tract, rendering them either transmission-incompetent or blocking their spread to untreated sentinels.

    The study’s limitations include uncertainty about whether the observed 4’-FlU resistance profile, determined in various experimental systems, equally applies to the human host.

    Conclusion

    In conclusion, the present study elucidates mechanisms diminishing the susceptibility of the IAV polymerase complex to 4’-FIU. In mice and ferret models, it is shown that while escape from 4’-FlU is possible, it is associated with viral attenuation and diminished transmission competence.

    Thus, 4’-FlU-resistant virus populations are found incapable of attaining clinical significance or enduring in circulation in real-world scenarios, highlighting the compound’s sustained therapeutic potential. In the future, studies exploring the potential human application and dose levels of 4’-FIU could be conducted.

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  • Do we simply not care about old people?

    Do we simply not care about old people?

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    The covid-19 pandemic would be a wake-up call for America, advocates for the elderly predicted: incontrovertible proof that the nation wasn’t doing enough to care for vulnerable older adults.

    The death toll was shocking, as were reports of chaos in nursing homes and seniors suffering from isolation, depression, untreated illness, and neglect. Around 900,000 older adults have died of covid-19 to date, accounting for 3 of every 4 Americans who have perished in the pandemic.

    But decisive actions that advocates had hoped for haven’t materialized. Today, most people — and government officials — appear to accept covid as a part of ordinary life. Many seniors at high risk aren’t getting antiviral therapies for covid, and most older adults in nursing homes aren’t getting updated vaccines. Efforts to strengthen care quality in nursing homes and assisted living centers have stalled amid debate over costs and the availability of staff. And only a small percentage of people are masking or taking other precautions in public despite a new wave of covid, flu, and respiratory syncytial virus infections hospitalizing and killing seniors.

    In the last week of 2023 and the first two weeks of 2024 alone, 4,810 people 65 and older lost their lives to covid — a group that would fill more than 10 large airliners — according to data provided by the CDC. But the alarm that would attend plane crashes is notably absent. (During the same period, the flu killed an additional 1,201 seniors, and RSV killed 126.)

    “It boggles my mind that there isn’t more outrage,” said Alice Bonner, 66, senior adviser for aging at the Institute for Healthcare Improvement. “I’m at the point where I want to say, ‘What the heck? Why aren’t people responding and doing more for older adults?’”

    It’s a good question. Do we simply not care?

    I put this big-picture question, which rarely gets asked amid debates over budgets and policies, to health care professionals, researchers, and policymakers who are older themselves and have spent many years working in the aging field. Here are some of their responses.

    The pandemic made things worse. Prejudice against older adults is nothing new, but “it feels more intense, more hostile” now than previously, said Karl Pillemer, 69, a professor of psychology and gerontology at Cornell University.

    “I think the pandemic helped reinforce images of older people as sick, frail, and isolated — as people who aren’t like the rest of us,” he said. “And human nature being what it is, we tend to like people who are similar to us and be less well disposed to ‘the others.’”

    “A lot of us felt isolated and threatened during the pandemic. It made us sit there and think, ‘What I really care about is protecting myself, my wife, my brother, my kids, and screw everybody else,’” said W. Andrew Achenbaum, 76, the author of nine books on aging and a professor emeritus at Texas Medical Center in Houston.

    In an environment of “us against them,” where everybody wants to blame somebody, Achenbaum continued, “who’s expendable? Older people who aren’t seen as productive, who consume resources believed to be in short supply. It’s really hard to give old people their due when you’re terrified about your own existence.”

    Although covid continues to circulate, disproportionately affecting older adults, “people now think the crisis is over, and we have a deep desire to return to normal,” said Edwin Walker, 67, who leads the Administration on Aging at the Department of Health and Human Services. He spoke as an individual, not a government representative.

    The upshot is “we didn’t learn the lessons we should have,” and the ageism that surfaced during the pandemic hasn’t abated, he observed.

    Ageism is pervasive. “Everyone loves their own parents. But as a society, we don’t value older adults or the people who care for them,” said Robert Kramer, 74, co-founder and strategic adviser at the National Investment Center for Seniors Housing & Care.

    Kramer thinks boomers are reaping what they have sown. “We have chased youth and glorified youth. When you spend billions of dollars trying to stay young, look young, act young, you build in an automatic fear and prejudice of the opposite.”

    Combine the fear of diminishment, decline, and death that can accompany growing older with the trauma and fear that arose during the pandemic, and “I think covid has pushed us back in whatever progress we were making in addressing the needs of our rapidly aging society. It has further stigmatized aging,” said John Rowe, 79, professor of health policy and aging at Columbia University’s Mailman School of Public Health.

    “The message to older adults is: ‘Your time has passed, give up your seat at the table, stop consuming resources, fall in line,’” said Anne Montgomery, 65, a health policy expert at the National Committee to Preserve Social Security and Medicare. She believes, however, that baby boomers can “rewrite and flip that script if we want to and if we work to change systems that embody the values of a deeply ageist society.”

    Integration, not separation, is needed. The best way to overcome stigma is “to get to know the people you are stigmatizing,” said G. Allen Power, 70, a geriatrician and the chair in aging and dementia innovation at the Schlegel-University of Waterloo Research Institute for Aging in Canada. “But we separate ourselves from older people so we don’t have to think about our own aging and our own mortality.”

    The solution: “We have to find ways to better integrate older adults in the community as opposed to moving them to campuses where they are apart from the rest of us,” Power said. “We need to stop seeing older people only through the lens of what services they might need and think instead of all they have to offer society.”

    That point is a core precept of the National Academy of Medicine’s 2022 report Global Roadmap for Healthy Longevity. Older people are a “natural resource” who “make substantial contributions to their families and communities,” the report’s authors write in introducing their findings.

    Those contributions include financial support to families, caregiving assistance, volunteering, and ongoing participation in the workforce, among other things.

    “When older people thrive, all people thrive,” the report concludes.

    Future generations will get their turn. That’s a message Kramer conveys in classes he teaches at the University of Southern California, Cornell, and other institutions. “You have far more at stake in changing the way we approach aging than I do,” he tells his students. “You are far more likely, statistically, to live past 100 than I am. If you don’t change society’s attitudes about aging, you will be condemned to lead the last third of your life in social, economic, and cultural irrelevance.”

    As for himself and the baby boom generation, Kramer thinks it’s “too late” to effect the meaningful changes he hopes the future will bring.

    “I suspect things for people in my generation could get a lot worse in the years ahead,” Pillemer said. “People are greatly underestimating what the cost of caring for the older population is going to be over the next 10 to 20 years, and I think that’s going to cause increased conflict.”

    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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