Tag: coronavirus

Study shows antipsychotic drugs increase health risks in dementia patients
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In a recent British Medical Journal study, researchers assess the adverse effects associated with the use of antipsychotic drugs in people with dementia.

Study: Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study. Image Credit: Fahroni / Shutterstock.com

The role of antipsychotics in dementia management

Individuals diagnosed with dementia undergo functional disability and progressive cognitive decline. Some common psychological and behavioral symptoms of dementia include anxiety, depression, apathy, aggression, delirium, irritability, and psychosis.

To manage psychological and behavioral symptoms of dementia, patients are commonly treated with antipsychotics. The United Kingdom National Institute for Health and Care Excellence currently recommends the use of antipsychotics only when non-drug interventions are ineffective in alleviating behavioral and psychological symptoms of dementia. However, there has been an increase in antipsychotic use during the recent coronavirus disease 2019 (COVID-19) pandemic, which has been attributed to lockdown measures and the unavailability of non-pharmaceutical treatments.

In the U.K., risperidone and haloperidol are the only antipsychotics that have received approval for the treatment of behavioral or psychological symptoms of dementia. In 2003, the United States Food and Drug Administration (FDA) highlighted the risks, such as stroke, transient ischaemic attack, and mortality, associated with the use of risperidone in older adults with dementia.

Based on multiple study reports, regulatory guidelines have been formulated in the U.K., U.S., and Europe to reduce inappropriate prescriptions of antipsychotic drugs for the treatment of behavioral and psychological symptoms of dementia. To date, few studies have provided evidence of the association between antipsychotic drug prescriptions in older adults with dementia and risks of multiple diseases, such as myocardial infarction, venous thromboembolism, ventricular arrhythmia, and acute kidney injury.

About the study

The current study investigated the risk of adverse outcomes associated with antipsychotics in a large cohort of adults with dementia. Some adverse outcomes considered in this study were venous thromboembolism, stroke, heart failure, ventricular arrhythmia, fracture, myocardial infarction, pneumonia, and acute kidney injury.

Over 98% of the U.K. population is registered with National Health Service (NHS) primary care general practice. All relevant data were collected from the electronic health records held at the Clinical Practice Research Datalink (CPRD), which is associated with over 2,000 general practices. CPRD comprises the Aurum and GOLD databases, which can be considered as broadly representative of the U.K. population.

Individuals above 50 years of age and diagnosed with dementia were recruited. Importantly, none of the study participants were under antipsychotic intervention one year before their diagnosis.

The researchers utilized a matched cohort design, in which each patient who used antipsychotics after their initial dementia diagnosis was matched using the incidence density sampling method. This method considered up to 15 randomly selected patients who were diagnosed with dementia on the same date but were not prescribed antipsychotic drugs.

Antipsychotics increase the risk of adverse effects in dementia patients

Across the two cohorts, the mean age of the participants was 82.1 years. A total of 35,339 participants were prescribed an antipsychotic during the study period.

The mean number of days between the first diagnosis of dementia and the date of a first antipsychotic prescription was 693.8 and 576.6 days for Aurum and GOLD, respectively. The most commonly prescribed antipsychotics were risperidone, haloperidol, olanzapine, and quetiapine.

The current population-based study revealed that adults with dementia prescribed antipsychotics are at a greater risk of venous thromboembolism, myocardial infarction, stroke, heart failure, pneumonia, fracture, and acute kidney injury than non-users. This observation was based on analyzing 173,910 adults with dementia selected from both databases.

The increased risk of adverse outcomes was most prevalent among current and recent users of antipsychotic drugs. After 90 days of antipsychotic use, the risk of venous thromboembolism, pneumonia, acute kidney injury, and stroke was higher than non-users. However, antipsychotic drugs did not impact the risk of ventricular arrhythmia, appendicitis, and cholecystitis.

As compared to the use of risperidone, haloperidol was significantly associated with an increased risk of pneumonia, fracture, and acute kidney injury. Although the adverse effects of haloperidol were higher than quetiapine, no significant differences were observed between risperidone and quetiapine for the risk of fracture, heart failure, and myocardial infarction. The risk of pneumonia, stroke, acute kidney injury, and venous thromboembolism was lower for quetiapine as compared to risperidone.

Conclusions

The current study highlights how antipsychotic drugs affect older adults with dementia. The use of these drugs was associated with many serious adverse outcomes, such as stroke, acute kidney injury, pneumonia, venous thromboembolism, heart failure, and myocardial infarction.

In the future, these risks must be considered, along with cerebrovascular events and mortality, while making regulatory decisions about the use of antipsychotic drugs for the treatment of dementia in older adults.
Journal reference:

Mok, L. H. P., Carr, M. J., Guthrie, B., et al. (2024) Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study. BMJ. doi:10.1136/bmj.2023.076268
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April 19, 2024
Seasonal influenza triggers significant school closures, especially in southern states, study finds

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In a recent study published in The Lancet Regional Health-Americas, researchers examined closures of United States (US) schools due to 11 influenza seasons between 2011 and 2022, determining the frequency and features of these closures.

Study: School closures due to seasonal influenza: a prospective data collection-based study of eleven influenza seasons—United States, 2011–2022. Image Credit: Inna Reznik/Shutterstock.com

Background

School closures are critical for avoiding influenza transmission and are often enforced ahead of time during severe pandemics. However, reactive, unforeseen closures occur every year during seasonal outbreaks.

A study conducted in 2009 found that around 2,000 schools closed during the fall wave. Existing data underscores the necessity of identifying and managing unforeseen school closures during pandemics, which reflect nationwide influenza activity.

About the study

In the current study, researchers analyzed seasonal influenza-related closures in US schools.

The researchers conducted a systematic daily web search from 1 August 2011 to 30 June 2022 to find public announcements of unanticipated school closings in the United States lasting ≥1.0 days. They selected those that listed influenza (Flu) and influenza-like illness (ILI) as reasons for closure.

They analyzed ILI-SC temporal trends and compared them to reported outpatient ILI-related healthcare visits. They excluded coronavirus disease 2019 (COVID-19)-related school closings. They extracted particular contributing elements from every ILI-SC announcement.

The team described a multi-year trend of ILI-associated school closings in the United States from 2011–2012 to 2021–2022, focusing on the temporal and geographical relationships between ILI-associated school closings and regular surveillance information on influenza and ILI requiring medical attention at the regional and national levels.

They additionally examined the pattern changes between data obtained before COVID-19 and data collected during the pandemic years.

The researchers analyzed two types of publicly accessible data: school information and the National Center for Education Statistics’ Common Core of Data.

They used publicly accessible information on district- and school-level characteristics from the National Center for Education Statistics (NCES) Common Core of Data (CCD) and the Private School Universe Survey (PSS), which revealed high coverage rates for conventional private schools. The researchers subsequently stratified districts by schools for ILI-SCs at the district level.

The team collected publicly accessible surveillance information on seasonal influenza activities, including weekly US Department of Health and Human Services region-specific and national data on the percentage of medical provider visits in outpatient departments for influenza-like illness (ILINet) across the United States.

They also collected national laboratory-verified influenza-associated hospitalization data for pediatric and adult individuals (FluSurv-NET) from 13 US states.

They used descriptive statistics to examine the features, seasonality, length, and geographical distribution of ILI-SCs and their influence on school closures, comparing weekly occurrence patterns to seasonal influenza-related surveillance information.

Results

The study found that ILI-SCs occur annually in over 100,000 US schools, with the highest connections identified during influenza A (H3N2)-dominant seasons.

These incidents generally occur in Region 4 of the United States Department of Health and Human Services and disproportionately affect rural and low-income populations. From 2011 to 2022, 2,077 school closures were due to influenza/ILI, with the most common reason being increased absence among pupils and staff owing to sickness.

Over the 11-year research period, these occurrences resulted in an estimated 9,136 school closures, affecting four million pupils and 260,000 instructors.

Before COVID-19, schools in rural regions were significantly more likely to experience ILI-SCs than schools in cities and towns.

Schools with large student populations participating in the federal free or reduced-price lunch program had a higher closing likelihood. The timing of ILI-SC incidence nationally concerning outpatient ILI activity differed between influenza seasons.

The highest connections between ILISCs and national outpatient healthcare visits for ILI occurred over the three seasons of 2016–2017 to 2018–2019, dominated by influenza A (H3N2). Truncation in the prior and succeeding weeks resulted in reduced correlations.

In the two full school years after the start of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, 2020-2021 and 2021-2022, 235 schools were closed as part of 58 ILI-SC incidents. All ILI-SCs in 2020–2021 were caused by ILI or COVID-19, with the 2020–2021 school year having the longest ILI-SCs.

Conclusions

The study found that seasonal influenza and ILI school closures are uncommon, and early notifications might improve influenza surveillance.

It offers situational awareness in real-time during severe outbreaks and tracks COVID-19-related closings of schools providing kindergarten through grade 12 education in the US between February 2020 and June 2022.

A multifaceted strategy, including enhanced immunization, improved ventilation, and prompt adoption of nonpharmaceutical therapies, should minimize ILI transmission before significant student absences lead to late reactionary school closures. The study also found that influenza-like disease epidemics occur regularly in the United States.

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April 18, 2024
Study reveals how SARS-CoV-2 hijacks lung cells to drive COVID-19 severity

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In a recent study published in the Journal of Experimental Medicine, researchers identified the cellular tropism and transcriptome consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by infecting human lung tissue and using single-cell ribonucleic acid sequencing (scRNA-seq) to rebuild the transcriptional program in “infection pseudotime” for distinct lung cell types.

Lower respiratory infections, such as coronavirus disease 2019 (COVID-19), are a leading cause of death worldwide, producing pneumonia and acute respiratory distress syndrome. Understanding their early phases is difficult. Researchers used classical histopathological approaches and single-cell multi-omic profiling to infer early phases in human pathogenesis from lung lavage, biopsy, or autopsy materials. These approaches reveal a thorough picture of COVID-19 pneumonia at unparalleled cellular and molecular resolution, implying infection models including alveolar epithelium, capillaries, macrophages, and myeloid cells.

Study: Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung. Image Credit: Dotted Yeti / Shutterstock

About the study

In the present study, researchers developed an experimental COVID-19 model to investigate early molecular processes and pathogenic mechanisms of SARS-CoV-2 infection at the cellular level in native tissues of the human lung.

The researchers established SARS-CoV-2’s cellular tropism and its unique and dynamic impacts on host cellular gene expression in specific types of lung cells. Prominent targets were lung-resident macrophages, of which one SARS-CoV-2 takes over transcriptomes, inducing a targeted host interferon (IFN) antiviral program, and several chemokines and pro-fibrotic and pro-inflammatory and cytokines signaling to various structural and immunological cells of the lung.

To determine the early stages of COVID-19 in human lungs, the researchers sliced lung tissue obtained from surgical specimens or organ donor individuals into thick sections and used them for tissue culture analysis. Subsequently, they exposed the tissues to the SARS-CoV-2 USA-WA1 2020 strain at 1.0 multiplicity of infection (MOI) for two hours before allowing the SARS-CoV-2 infection to continue for two to three days. They performed a plaque test on culture supernatants.

The researchers separated the slices and examined them by scRNA-seq to evaluate host and viral genetic expression during the SARS-CoV-2 infection. They also examined the viral RNA molecules’ junctional structure and processing by analyzing the scRNA-seq dataset with the SICILIAN framework. They used molecular atlas markers to distinguish lung cell types in healthy lung slices and measure viral RNA levels in infected cells.

The team performed multiplexed single-molecule fluorescence in situ hybridization (smFISH) to confirm lung cell tropism findings and show infected cells. They used single-cell gene expression patterns to identify cellular targets for inflammatory and pro-fibrotic signals elicited by the SARS-CoV-2 infection of a-IMs. They devised a technique for purifying macrophage populations from human lungs with a SARS-CoV-2 spike (S) protein-pseudotyped lentivirus (lenti-S-NLuc-tdT) to investigate lung macrophage entrance routes.

The researchers productively infected human lung slices cultivated ex vivo with SARS-CoV-2, with production rising between 24 and 72 hours of culture. They heat-inactivated, ultraviolet (UV)-treated, or administered 10.0 µM remdesivir, an RNA-dependent RNA polymerase inhibitor used as a COVID-19 therapeutic, to prevent viral stock infection.

Results

The analysis showed that SARS-CoV-2 preferentially infects active interstitial macrophages (IMs), which can amass hundreds of SARS-CoV-2 RNA molecules, comprising >60% of the cell transcriptome and producing dense viral RNA bodies. Infected alveolar macrophages (AMs) exhibit no severe reactions, with spike (S) protein-dependent viral entrance into AMs utilizing angiotensin-converting enzyme 2 (ACE2) and the cluster of differentiation 169 (CD169) and IM entry via CD209.

They found canonical sub-genomic junctions between the unusual sequence reads beyond their 39 terminal regions, indicating canonical-type SARS-CoV-2 messenger RNA (mRNA) production in the pulmonary cultures. They also found hundreds of new subgenomic junctions, showing a wide range of non-canonical and canonical sub-genomic SARS-CoV-2 RNAs produced during pulmonary infection.

Model of initiation, transition, and pathogenesis of COVID-19 and the viral lifecycle in AMs and IMs. (a–d) Model of COVID-19 initiation in the human lung and transition from viral pneumonia to lethal COVID-19 ARDS. (a) SARS-CoV-2 virion dissemination and arrival in the alveoli. Luminal AM encounter virions shed from the upper respiratory tract that enter the lung. AMs can express low to moderate numbers of viral RNA molecules and can propagate the infection but “contain” the viral RNA from taking over the total transcriptome and show only a very limited host cell inflammatory response to viral infection. (b) Replication and epithelial injury. SARS-CoV-2 virions enter AT2 cells through ACE2, its canonical receptor, and “replicate” to high viral RNA levels, producing infectious virions and initiating viral pneumonia. (c) a-IM takeover and inflammation signaling. SARS-CoV-2 virions spread to the interstitial space through either transepithelial release of virions by AT2 cells or injury of the epithelial barrier, and enter a-IMs. Infected a-IMs can express very high levels of viral RNA that dominate (“take over”) the host transcriptome and can propagate the infection. Viral takeover triggers induction of the chemokines and cytokines shown, forming a focus of inflammatory and fibrotic signaling. (d) Endothelial breach and immune infiltration. The a-IM inflammatory cytokine IL6 targets structural cells of the alveolus causing epithelial and endothelial breakdown, and the inflammatory cytokines recruit the indicated immune cells from the interstitium or bloodstream, which flood and infiltrate the alveolus causing COVID-19 ARDS. Local inflammatory molecules are amplified by circulating immune cells, and reciprocally can spread through the bloodstream to cause systemic symptoms of cytokine storm. (e) Comparison of the SARS-CoV-2 viral lifecycle in AMs and IMs. Although both can produce infectious virions, note differences in viral entry receptors (AMs can use ACE2 and CD169/SIGLEC1, whereas IMs use CD209); viral RNA transcription of dsRNA intermediates (greater in AMs); replication of full-length genomic RNA (greater in IMs); viral takeover, formation of RNA bodies, and induction of a robust host cell inflammatory response (only in IMs), and cell destruction/death (only in IMs).

Heat, UV-C inactivation, or remdesivir therapy prevented the development of canonical and non-canonical connections. The team observed SARS-CoV-2 takeover of an activated IM subtype in 176,382 cells with high-quality transcriptomes obtained from infected lung slices of four donor lungs and in 112,359 cells from mock-infected slices (cultured without viral addition) and 95,389 uncultured control cells (directly from freshly cut lung slices). A differential gene expression study of a-IMs over infection pseudotime revealed host gene expression alterations corresponding to SARS-CoV-2 RNA levels.

The study found that COVID-19 pneumonia infection and takeover cause an early antiviral cell response specific to activated interstitial macrophages, resulting in a powerful immunological and fibrotic signaling center. Inflammasome activation is uncommon and only detectable late in a-IM infection. Blocking antibodies against CD169 and CD209 prevented entrance into IMs and AMs. The study also highlighted IMs as the most vulnerable lung target, with initial emphasis on inflammation and fibrosis. Two unique molecular lineages of macrophage targets react differently to SARS-CoV-2, influencing etiology and treatments.

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April 15, 2024
Annual COVID-19 vaccine proves to be a wise investment for personal health and pocketbook
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In a recent study published in The Journal of Infectious Diseases, a team of researchers from the United States (U.S.) attempted to understand whether individuals experienced any economic benefits in getting an annual coronavirus disease 2019 (COVID-19) vaccine, given that the morbidity and mortality rates associated with the disease have decreased and the government no longer covers the vaccine costs.

Study: What is the economic benefit of annual COVID-19 vaccination from the adult individual perspective? Image Credit: eamesBot / Shutterstock

Background

The rapid development of vaccines to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has helped significantly reduce the disease’s severity and limit the transmission of the virus. Although subvariants of SARS-CoV-2 continue to emerge and circulate, the virus’s virulence and transmissibility seem to have reduced due to the protection afforded by large-scale vaccination efforts worldwide.

With the drop in hospitalization and mortality rates, COVID-19 is no longer considered a significant public health risk, leading to a substantial decrease in vaccination rates across the U.S. Furthermore, employment organizations and businesses are no longer mandating booster COVID-19 vaccination shots. With the government no longer funding the cost of the vaccine, individuals have to pay for the COVID-19 booster shots either out-of-pocket or through their insurance. However, the gradual decrease in vaccination coverage and waning of infection-induced immunity could influence the control of viral transmission and disease severity.

About the study

In the present study, the researchers examined the benefits of getting annual COVID-19 vaccines, similar to the influenza vaccine, from an individual perspective instead of from the perspective of a third-party payer or society, which has already been examined in previous studies. The researchers believe that while the findings might not contribute to recommendations and decisions made by governments or insurance companies, they will help individuals assess the merits of an annual COVID-19 vaccination from their perspective.

The study developed and used a Markov computational simulation model to assess the values and trade-offs of getting the annual vaccine. This model used eight mutually exclusive states of SARS-CoV-2 infections and the economic and clinical outcomes for each state.

The state at which an individual begins is the state of no infection with pre-existing protection from previous vaccinations or infections. Based on factors such as risk of infection, probability of clinical outcomes based on age, and pre-existing protection levels, the model calculates the probability of an individual moving to a COVID-19 state. The model also calculates the probabilities of returning to the non-infected state or developing long COVID based on various levels of symptoms ranging from asymptomatic to severe.

These probabilities are calculated twice for each individual, once with and once without the annual COVID-19 vaccination. Minor to severe adverse effects, as well as changing vaccine efficacy, are also factors that are incorporated into the model. The economic measures are calculated based on factors such as loss of productivity due to vaccination absenteeism, mortality, out-of-pocket costs, presenteeism, healthcare visits, and medications. The cost-benefits were calculated for each scenario. Sensitivity analyses were also conducted for varying disease severity based on different SARS-CoV-2 variants.

Results

The results suggested that an individual stood to benefit clinically and economically by getting vaccinated annually against COVID-19. The model showed that adults between the ages of 18 and 49 saved an average of $30 to $603 if they did not have health insurance, while insured individuals of the same age group saved $4 to $437.

These estimates were on the assumption that the efficacy of the vaccine against SARS-CoV-2 started at greater than or equal to 50%, the individuals interacted with about nine people a day, the infection probability was more significant than or equal to 0.2%, the infection prevalence was 10%, and the conditions were for the Omicron variant of SARS-CoV-2 during the winter of 2023-2024.

For individuals between the ages of 50 and 64, the average economic benefits were even higher, with savings of $119 to $1706 and $111 to $1278 for individuals with and without insurance, respectively. Furthermore, in cases where the previous vaccination was nine months ago, and 13.4% of the pre-existing protection remained, the model showed that the risk threshold was greater than or equal to 0.4%.

Conclusions

Overall, the study found that the annual COVID-19 vaccine was economically and clinically beneficial to individuals with or without health insurance. The economic value of getting the COVID-19 vaccine was higher for individuals between 50 and 64 years of age.
Journal reference:

Bartsch, S. M., O’Shea, K. J., Weatherwax, C., Strych, U., Velmurugan, K., John, D. C., Bottazzi, M. E., Hussein, M., Martinez, M. F., Chin, K. L., Ciciriello, A., Heneghan, J., Dibbs, A., Scannell, S. A., Hotez, P. J., & Lee, B. Y. (2024). What is the economic benefit of annual COVID-19 vaccination from the adult individual perspective? The Journal of Infectious Diseases. DOI: 10.1093/infdis/jiae179, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiae179/7641782
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April 11, 2024
Nirmatrelvir fails to shorten COVID-19 symptoms in latest trial
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In a recent study published in The New England Journal of Medicine, researchers evaluate the efficacy of nirmatrelvir in combination with ritonavir against the coronavirus disease 2019 (COVID-19).

Study: Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19. Image Credit: Alexsey t17 / Shutterstock.com

A brief history of COVID-19 patient care

Since its emergence at the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has infected almost 700 million individuals and claimed over seven million lives worldwide. COVID-19 is associated with a wide range of pathologies in different populations, with the very young and elderly at the most significant risk of mortality and morbidity.

Rapid global medical research and vaccination programs have significantly reduced the burden of COVID-19 by attenuating SARS-CoV-2 transmission. Currently, COVID-19 patients are treated symptomatically through general antiviral interventions; however, an extensive search for a COVID-19-specific cure is still in the clinical trials phase.

Nirmatrelvir is an orally administered antiviral agent that inhibits the SARS-CoV-2 main protease (M^pro), which is critical for viral replication. Nirmatrelvir is administered with the pharmacokinetic enhancer ritonavir to inhibit metabolism by CYP3A4.”

One of the most promising antiviral therapies currently in clinical trials is the combination of nirmatrelvir and ritonavir. In unvaccinated adults, phase II and III clinical trials have produced promising results by reducing COVID-19 mortality risk by over 80%. Nevertheless, the anti-COVID-19 benefits of this intervention in vaccinated individuals remain unverified.

About the study

In the current study, researchers evaluate the efficacy and side effects of nirmatrelvir-ritonavir in non-hospitalized patients of various ages, ethnicities, and infection severity.

Data were obtained from the Evaluation of Protease Inhibition for Covid-19 in Standard-Risk Patients (EPIC-SR) trial, which is a randomized, double-blind, and placebo-controlled trial involving adult participants 18 years of age and older with laboratory reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed COVID-19. Individuals were enrolled in the study between August 2021 and July 2022 if their symptoms initially appeared in the five days prior to study enrollment.

Study participants were randomly assigned to receive either the nirmatrelvir-ritonavir intervention, which comprised 300 mg of nirmatrelvir and 100 mg of ritonavir, or placebo. The dosage was fixed once every 12 hours for five days, thus leading to a final total of 10 doses.

For statistical analyses, randomization was stratified across vaccination status, geographic region, and COVID-19 symptom onset. Data collection included participants’ sociodemographic, anthropometric, and medical records.

Digital diaries were also used to record daily intervention use, COVID-19 symptom severity on a four-point scale, and associated side effects. Efficacy measurements were conducted through day 34.

Sustained alleviation was considered to have occurred on the first of four consecutive days during which all symptoms that had been scored as moderate or severe and as mild or absent at baseline were scored as mild or absent and as absent, respectively.”

Study findings and relevance

Of the 1,296 participants initially enrolled in the study, 1,288 individuals, 654 of whom received nirmatrelvir-ritonavir and 634 placebo, provided completed data and were included in the statistical analyses. The study cohort primarily comprised women and individuals of the White ethnicity at 54% and 78.5%, respectively.

About 57% of the study cohort were vaccinated, with smoking as the most commonly severe COVID-19 risk factor reported among 13.3% of the study participants. Study intervention compliance was high across both cohorts at 94.8% and 96.5% for nirmatrelvir-ritonavir and placebo, respectively.

Efficacy evaluations revealed no statistically different outcomes between nirmatrelvir-ritonavir and placebo treatment cohorts. While the safety evaluation found no statistically significant differences between the side effects reported across trial groups, dysgeusia, diarrhea, and nausea were often reported by those who received nirmatrelvir-ritonavir during the study.

Conclusions

The study findings suggest that nirmatrelvir-ritonavir may not be as effective as suspected in alleviating adverse viral SARS-CoV-2 outcomes, especially in symptomatic, non-hospitalized, vaccinated, or unvaccinated adults. Given the known and study-reported side effects, nirmatrelvir-ritonavir cannot yet be established as a safe and beneficial treatment for severe COVID-19 outpatients, irrespective of prior vaccination status.

Nirmatrelvir–ritonavir was not associated with a significantly shorter time to sustained alleviation of COVID-19 symptoms than placebo, and the usefulness of nirmatrelvir–ritonavir in patients who are not at high risk for severe COVID-19 has not been established.”
Journal reference:

Hammond, J., Fountaine, R. J., Yunis, C., et al. (2024). Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19. The New England Journal of Medicine 390(13); 1186-1195. doi:10.1056/nejmoa2309003
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April 9, 2024
Pioneering vaccine strategy promises to outmaneuver antimicrobial resistance
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In a recent study published in the journal Npj Vaccines, researchers presented the method of Reverse Vaccine Development, which provides an opportunity to determine the correlates of protection in the early stages of clinical trials for vaccines against pathogens that are resistant to antimicrobial agents to prevent problems such as significant phase-III clinical trial failures, loss of investment in vaccine development, and populations being exposed to ineffective vaccines.

Perspective: Reverse development of vaccines against antimicrobial-resistant pathogen. Image Credit: Kateryna Kon / Shutterstock

Background

The development of antimicrobial resistance in pathogens is rapidly becoming a public health concern of the same or possibly higher magnitude as malaria or human immunodeficiency virus (HIV). However, the process of developing vaccines is tedious and expensive, and in the case of antimicrobial-resistant pathogens, it is made worse by inadequate information on correlates of protection.

In the case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the process of vaccine development was significantly accelerated by the discovery of antibodies that could bind to the spike protein of the virus, preventing it from binding to the host angiotensin-converting enzyme-2 receptor. This discovery also indicated that neutralizing antibody titers could be used as correlates of protection since they indicated the clinical efficacy of the vaccine.

For most antimicrobial-resistant pathogens, the mechanisms through which vaccines can protect the host remain unknown. While immunomics, proteomics, and genomics are being extensively used to develop vaccines against antimicrobial-resistant pathogens, the dearth of information on correlates of protection continues to present the risk of jeopardizing late-stage clinical trials.

About the study

In the present study, the researchers presented a method of Reverse Vaccine Development, a new paradigm for vaccine development that requires information on the efficacy of the vaccine and the immune responses to be generated much earlier in the vaccine development process so that the correlates of protection can be identified early on instead of closer to phase III trials. They also implemented this paradigm to evaluate a vaccine against the antimicrobial bacteria Staphylococcus aureus.

The process is called Reverse Vaccine Development since the order of information procurement on vaccine efficacy is reversed as compared to the typical procedure of vaccine development. This information is obtained from populations that are already experiencing a high incidence of antimicrobial-resistant pathogenic infections instead of the population that will eventually get vaccinated.

Paradigm clinical trial design (phase 1/2) in Reverse Vaccine Development: S. aureus vaccine in subjects at high risk of SSTI.

Given that animal models have not been unreliable in vaccine development against antimicrobial-resistant pathogens, using high-risk populations helps compare the immune responses of unprotected and protected individuals, which can provide data on correlates of protection.

The efforts to develop vaccines against S. aureus have yielded four candidate vaccines that target various antigens and use four different protection mechanisms. Based on the results from animal model studies and in-vitro assays, the vaccines were advanced to phase I and II clinical trials. The vaccines passed the safety assessments and elicited satisfactory antibody titers. However, the phase III efficacy trials for these vaccines failed, indicating a lack of adequate information on correlates of protection.

To circumvent such problems, the researchers in this study applied the paradigm of Reverse Vaccine Development to design a randomized, observer-blinded, placebo-controlled phase I and II trials to assess the immunogenicity, safety, and efficacy of the candidate vaccine developed against S. aureus by GSK.

Results

The study discussed how Reverse Vaccine Development differs from the traditional vaccine development process by beginning in phase I or II trials that evaluate the efficacy, immunogenicity, and safety of the vaccine instead of efficacy evaluation in phase III trials. This ensures that potential problems associated with correlates of protection are identified early in the vaccine development process and do not result in the failure of the vaccine towards the end stages when considerable resources have been invested in the process.

Phase I safety trials with and without adjuvant are often conducted if the vaccine is being developed for the first time for humans, and based on the results of the phase I safety assessments, the trial proceeds into phase II to evaluate the efficacy and immunogenicity. Comparing the immune responses elicited by the vaccine among unprotected and protected groups can help identify correlates of protection, which can then be used to formulate, schedule, and facilitate vaccine efficacy assessments in the general populations and refine the vaccine dosage.

The researchers discussed in detail the various parameters that need to be evaluated when correlates of protection are being explored. These included serology, cellular responses, immunological signals, transcriptional profiles, memory immune cell responses, and background immunity.

Conclusions

To summarize, the study described a novel vaccine development paradigm that involves conducting phase I and II trials in populations that are at high risk of contracting the target antimicrobial-resistant pathogen to understand the correlates of protection before the development process progresses to phase III trials and risks failure. This method could circumvent grave problems in vaccine development, such as exposure to inefficacious vaccines and the loss of resource investment.
Journal reference:

Bagnoli, F., Galgani, I., Kumaran, V. V., & Phogat, S. (2024). Reverse development of vaccines against antimicrobial-resistant pathogens. Npj Vaccines, 9(1), 71. 10.1038/s41541024008584, https://www.nature.com/articles/s41541-024-00858-4
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April 8, 2024
Feeling lonely? It may affect how your brain reacts to food, new research suggests
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In a recent study published in JAMA Network Open, researchers investigated the associations between individuals’ perceived levels of social isolation and brain patterns related to food cues, psychological outcomes, and obesity.

Their results indicate that loneliness can lead to challenges in control and motivation when responding to foods and have important implications for the development of effective treatments for obesity.

Study: Social Isolation, Brain Food Cue Processing, Eating Behaviors, and Mental Health Symptoms. Image Credit: Mansoreh/Shutterstock.com

Background

Perceived social isolation, or loneliness, is known to have significant impacts on health, including mental health disorders, cardiovascular disease, and obesity. The negative health consequences of social isolation were widely documented during the coronavirus disease 2019 (COVID-19) pandemic.

The biological mechanisms that underlie loneliness include alterations in brain networks like the default mode network, executive control network, visual attention network, and reward network, which could lead to hypervigilance to perceived social threats, heightened self-rumination, and increased sensitivity to negative social cues.

They may also contribute to maladaptive behaviors like overeating and substance cravings.

Investigating the neural mechanisms that link loneliness to alterations in responses to food cues may yield important insights into what scientists have termed the ‘lonely brain’ phenomenon.

About the study

In this study, researchers hypothesized that loneliness is associated with increased activation in certain brain regions when viewing food cues, which correlates with worsened mental health, changed eating behaviors, and obesity measures.

Another key hypothesis was that sweet food-related neural alterations would show stronger associations with maladaptive eating behaviors and mental health outcomes due to the well-documented rewarding nature of sugar-rich foods.

Healthy, premenopausal female participants were recruited in Los Angeles and asked to report perceived social isolation using the Perceived Isolation Scale.

They went through functional magnetic resonance imaging (fMRI) while being exposed to various food cues to evaluate neural responses to different food types.

Various clinical and behavioral measures were examined, including body composition, eating behaviors, and mental health variables.

Statistical analyses were conducted to compare demographic and clinical characteristics between high and low-perceived isolation groups. Whole-brain analyses were performed to assess perceived isolation-related differences in neural responses to the cues.

Regions of interest (ROIs) were identified, and brain signal changes were extracted for further analysis. Multiple linear regression analyses examined associations between loneliness-related brain food cue reactivity and individual clinical and behavioral measures.

Mediation analyses were conducted to assess the mediating effect of brain food cue reactivity on the association between perceived isolation and various outcomes of interest, such as body measurements, eating behaviors, and mental health. All analyses were adjusted for age.

Findings

Overall, 93 female participants aged 18 to 50 years, with a mean age of 25.38 years, were included, with 41% self-identifying as Filipino and 59% as Mexican.

The high perceived isolation group (n=39) exhibited poorer diet quality, greater fat mass percentage, poorer mental health, and increased maladaptive eating behaviors compared to the low perceived isolation group (n=54).

The findings from whole-brain comparisons showed that the group perceiving higher levels of social isolation reacted significantly more strongly to cues when viewing foods compared to non-foods, particularly in the region of the inferior parietal lobule (IPL).

Specifically, when they viewed sweet foods compared to non-foods, increased reactivity was observed in multiple brain regions, including the lateral occipital cortex, inferior frontal gyrus, and IPL.

Conversely, when they were shown savory foods compared to non-foods, the group perceiving higher levels of isolation exhibited less reactivity to cues in the dorsolateral prefrontal cortex (dlPFC) and central praecuneus.

Brain reactivity to sweet groups only and all food groups was correlated with mental health indicators and maladaptive food consumption behaviors. However, no associations were found for the subsample of savory foods.

When participants were shown food compared to non-food, brain reactivity was observed to mediate the correlations with reward-based eating, food cravings, and generally maladaptive eating behaviors.

Similarly, when participants viewed sweet food compared to non-food, brain reactivity was seen to mediate associations with body fat percentage, reward-based eating, food cravings, and generally maladaptive eating behaviors.

The association between viewing savory food and positive affect was also mediated by brain reactivity.

Conclusions

This study reveals that loneliness is linked to obesity, mental health symptoms, and maladaptive eating behaviors.

Being lonely was associated with increased body fat; lonely individuals were also more likely to report maladaptive eating behaviors and increased vulnerability to psychological symptoms.

Brain imaging showed heightened reactivity to cues in brain regions associated with social cognition and executive control, suggesting an imbalance in sensitivity to internal states and external cues.

Sweet foods particularly influenced neural responses, potentially due to their rewarding nature and analgesic effect.

These findings underscore the role of altered brain processing in mediating the association between social isolation and adverse health outcomes, highlighting the importance of holistic interventions targeting both body and mind.
Journal reference:

Zhang, X., Ravichandran, S., Gee, G.C., Dong, T.S., Beltrán-Sánchez, H., Wang, M.C., Kilpatrick, L.A., Labus, J.S., Vaughan, A., Gupta, A. (2024) Social isolation, brain food cue processing, eating behaviors, and mental health symptoms. JAMA Network Open. doi:10.1001/jamanetworkopen.2024.4855.https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2817148
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April 5, 2024
Novel SARS-CoV-2 mutations found in floodwaters near homeless communities
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In a recent study published in the journal Environmental Science & Technology Letters, researchers conducted environmental surveillance to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in two flood control channels in the United States (US), influenced by homeless individuals. They detected SARS-CoV-2 RNA (short for ribonucleic acid) and novel spike gene mutations in the channels during COVID-19 (short for coronavirus disease 2019) outbreaks, emphasizing the efficacy of environmental surveillance for assessing public health in the homeless population.

Study: Environmental Surveillance of Flood Control Infrastructure Impacted by Unsheltered Individuals Leads to the Detection of SARS-CoV-2 and Novel Mutations in the Spike Gene. Image Credit: CROCOTHERY / Shutterstock

Background

During the COVID-19 pandemic, overwhelmed public health laboratories in the US prompted the initiation of the National Wastewater Surveillance System (NWSS) to support traditional surveillance efforts in March 2020. The program could effectively detect SARS-CoV-2 RNA, antimicrobial resistance markers, and emerging variants, offering early detection for public health priorities. Several studies have reported the presence of viruses and human fecal material in flood control channels due to various factors like overflowing sanitary sewers and direct human inputs. In cities where homelessness is common, environmental surveillance of flood control channels can aid in understanding disease transmission among people experiencing homelessness, which is often overlooked in clinical surveillance data.

RNA of SARS-CoV-2 can sustain in water bodies for extended periods, while infected individuals can continue shedding significant amounts of viral RNA in fecal matter for up to seven months. Despite previous research demonstrating the presence of SARS-CoV-2 RNA in surface waters, conducting whole genome sequencing (WGS) from flood control channels for variant identification is less frequent, primarily due to difficulties in collecting and analyzing samples. Researchers in the present study aimed to identify SARS-CoV-2 RNA in environmental water samples from flood control infrastructure impacted by homeless individuals, perform WGS, compare variants with those found in the local community, and potentially reveal any novel mutations.

About the study

In the present study, water sample processing was performed by concentrating primary effluent from wastewater treatment plants (WWTPs) using hollow fiber ultrafiltration, followed by extraction and synthesis of cDNA (short for complementary deoxyribonucleic acid). Environmental water samples from two sources (Flamingo Wash and Tropicana Wash) were processed similarly. A total of 57 samples were collected and analyzed.

SARS-CoV-2 RNA quantification was performed using quantitative polymerase chain reaction (qPCR). Further, library preparation for amplicon-based WGS made use of a SARS-CoV-2 panel and Illumina NextSeq 500. Data analysis included adapter trimming, read alignment, primer masking, variant calling, and determination of variant composition. Low-frequency and novel mutations were identified and validated using various databases.

Results and discussion

SARS-CoV-2 RNA was detected in 15 samples (33% in treated water and 20% in freshwater), with concentrations between 2.8 and 4.8 log10 gc/L. Higher detection frequencies occurred in the first two months of 2022, corresponding to the peak of the first Omicron wave. This aligns with the maximal concentrations observed at the WWTP. PMMoV (short for pepper mild mottle virus), a fecal indicator virus, was detected in almost all samples, with concentrations between 4.0 and 6.3 log10 gc/L, consistent with previous studies. Detection frequencies of PMMoV were slightly higher in this study than in earlier ones, possibly due to the increased sensitivity of sample processing methods or the study of areas with higher densities of unsheltered individuals.

The detected variants were majorly classified as Omicron, Delta, and Alpha, especially in environmental water samples. Notably, Alpha detection in freshwater indicated potential persistent shedding or low circulation levels. Delta variant signals were observed, correlating with shedding timelines, suggesting variable loadings could influence variant composition in environmental samples.

Previously unreported mutations of the SARS-CoV-2 spike protein, including Tyr636Phe, Ser943Thr, and Phe1103Val, were identified in the samples. These mutations, not residing in the receptor-binding domain (RBD), were observed more than once, with Tyr636Phe being the most frequently detected. While the origin and significance of these mutations remain uncertain, their presence suggests potential circulation within the local community rather than being unique to flood control channels or municipal wastewater.

The findings suggest that COVID-19 transmission within unsheltered populations may reflect trends in the general community. However, a direct comparison of variant prevalence could not be made due to limited clinical surveillance data for unsheltered individuals.

Conclusion

In conclusion, the study found that the SARS-CoV-2 variants detected in environmental water samples influenced by human waste from homeless individuals were like those circulating in the broader community, as observed through wastewater and clinical surveillance. The highest concentrations of SARS-CoV-2 RNA coincided with the peak of the initial Omicron surge, followed by a decline correlating with decreased wastewater concentrations and confirmed case counts. The study emphasizes the utility of environmental surveillance for understanding public health conditions and infectious disease transmission, particularly among vulnerable homeless populations.
Journal reference:

Environmental Surveillance of Flood Control Infrastructure Impacted by Unsheltered Individuals Leads to the Detection of SARS-CoV-2 and Novel Mutations in the Spike Gene. Anthony Harrington et al., Environmental Science & Technology Letters (2024), DOI: 10.1021/acs.estlett.3c00938, https://pubs.acs.org/doi/10.1021/acs.estlett.3c00938
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April 5, 2024
What is Disease X and do we need to worry about it?

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What is Disease X?

Don’t panic! Disease X doesn’t exist yet – but it might one day. Disease X is the label that the World Health Organization uses to refer to some currently unknown infectious condition that is capable of causing an epidemic or – if it spreads across multiple countries – a pandemic. The term, coined in 2017, can be used to mean a newly discovered pathogen or any known pathogen with newly acquired pandemic potential. By the latter definition, covid-19 was the first Disease X. But there could be another in the future.

Why are people talking about it now?

The World Health Organization has been warning global leaders about the risks of future pandemics at the World Economic Forum’s annual meeting. “Some people say this may create panic,” says WHO director-general Tedros Adhanom Ghebreyesus. “No. It’s better to anticipate something that may happen – because it has happened in our history many times – and prepare for it.”

What might the next Disease X be?

We don’t know – that is why it is called Disease X. The coronaviruses, a large group of viruses, were long seen as a prime contender for producing a new pandemic, even before the covid-19 outbreak. That is because the novel coronavirus wasn’t the first dangerous pathogen from this group. In 2002, a different coronavirus started spreading in China. It caused a form of pneumonia called SARS that killed around 1 in 10 of those it infected, before it was stopped by strict infection control measures. Another, even deadlier coronavirus called MERS occasionally breaks out, causing a pneumonia that kills 1 in 3 of those infected. However, recent work suggests SARS and MERS would have a harder time triggering a fresh pandemic because almost everyone in the world now has antibodies to the virus that causes covid-19 and these seem to give partial protection against most other pathogens in the coronavirus family.

Are there any other contenders with pandemic potential?

Plenty of diseases, some well known and others less familiar, could pose a global threat. Flu strains have caused global pandemics several times in the past, including one of the deadliest disease outbreaks ever, the “Spanish flu” of 1918. A virulent strain of bird flu is currently sweeping the world, and it occasionally spreads from birds to mammals, causing mass die-offs. Just this week, it was named as the culprit in the deaths of 17,000 baby elephant seals in Argentina last October. Then there are other contenders, such as Ebola, which causes severe bleeding, and the mosquito-borne Zika, which can cause babies to born with smaller heads if the infection occurs during pregnancy. The WHO updated its list of pathogens with the most pandemic potential in 2022.

What can we do to stop Disease X?

There is some good news: the covid-19 pandemic may have made it easier to stop any future Disease X. Covid-19 spurred the development of novel vaccine designs, including ones that can be quickly repurposed to target new pathogens. It led, for instance, to the advent of vaccines based on mRNA. This formula contains a short piece of genetic material that makes the body’s immune cells produce the coronavirus “spike” protein – but it could be updated to make cells churn out a different protein, simply by rewriting the mRNA sequence.

Can we do anything else to fight against Disease X?

Countries need better early warning systems for new diseases, and health services need to become more resilient to unexpected surges in demand, says Tedros. “When hospitals were stretched beyond their capacity [with covid], we lost many people because we could not manage them. There was not enough space, there was not enough oxygen.” To prevent the same thing from happening when Disease X strikes, Tedros says health services must be able to expand their capacity on demand. Luckily, they can make those preparations without knowing exactly what Disease X will be. “Disease X is a placeholder,” he says. “Whatever the disease is, you can prepare for it.”

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April 4, 2024
New study reveals increased risk of allergic diseases after COVID-19 infection
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A recent study published in Nature Communications explored the association of COVID-19 with long-term allergic conditions.

Study: Incident allergic diseases in post-COVID-19 condition: multinational cohort studies from South Korea, Japan and the UK. Image Credit: wavebreakmedia/Shutterstock.com

Background

The severe respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019, and led to the declaration of a coronavirus disease 2019 (COVID-19) pandemic in March 2020. It caused over seven million deaths and many times that number of infections and hospitalizations.

Additionally, nearly half of COVID-19 cases have to deal with delayed or chronic morbidity, which may have set in during or after the acute phase of infection. These are called post-COVID-19 conditions or post-acute sequelae of COVID-19 (PASC), otherwise known as long COVID.

Symptoms of PASC, in some cases, include immunologic phenomena that may cause allergic conditions of various kinds.

About the study

The study aimed to investigate how ethnicity affects allergic conditions following COVID-19. Researchers formed a synthetic group comprising over 22 million individuals from South Korea, Japan, and the UK, drawing participants from multinational studies to represent these ethnic backgrounds. S

pecifically, the South Korean segment included more than 800,000 people with an average age of 48. From the UK and Japan, the cohorts included over 325,000 and 2.5 million participants, respectively.

Within these groups, approximately 150,000 participants from South Korea, 77,000 from the UK, and 542,000 from Japan had been infected with SARS-CoV-2. This large-scale analysis aimed to shed light on the ethnic variations in post-COVID-19 allergic reactions.

What were the findings?

After adjusting for all known variables that could affect the outcome, the researchers discovered that individuals infected with SARS-CoV-2 showed a 20% higher occurrence of allergic diseases compared to those not infected.

This increased risk was consistent for infections from both the original and Delta variants of the virus. Specifically, the likelihood of developing asthma in those infected was more than double, at 2.25 times that in non-infected individuals.

The chance of getting allergic rhinitis was 25% higher in the infected group, though no significant increase was observed for food allergies or atopic dermatitis.

Moreover, while the risk for allergic diseases decreased over time after the infection, it didn’t disappear entirely. This decrease in risk varied from country to country.

Severity of infection and allergy risk

Moderate-to-severe COVID-19 was linked to a 50% higher risk of overall allergy, compared to 14% among those with mild disease.

COVID-19 vaccination and allergy risk

Those who had received the vaccine had a 44% higher risk of allergy (with one dose). This was reduced by 20% after two doses of the vaccine. The two-dose cohort had comparable allergy risk as the controls, both overall and for the various allergy subgroups.

Other factors like coexisting morbidity, drinking, body mass index, exercise, and the SARS-CoV-2 strain responsible for the infection, did not show significant correlation with allergy risk.

Conclusions

“This is the first study that provides comprehensive evidence for the association between SARS-CoV-2 infection and subsequent incident allergic outcomes.”

It emphasizes the relationship between COVID-19, especially moderate to severe, and subsequent allergy onset. It also indicates that COVID-19 vaccination with at least two doses weakens the risk of new allergies.

The findings broadly corroborate earlier research, but there is a need for more studies on the allergic sequelae of COVID-19 on a larger and more multinational scale.

Multiple pathways have been proposed to account for the observed correlations, including T cell disruption, regulatory T cell (Treg) disturbances, and the cytokine storm in acute severe COVID-19.

Over time, the virus may be slowly cleared from the host, especially if adaptive immunity has been strengthened by vaccination against the virus.

The study underlines “a need for persistent health policies to manage the severity of SARS-CoV-2 infection.” People with a history of COVID-19 should be aware that they are at higher risk for allergic manifestations in the short-term future, at least.
Journal reference:

Oh, J., Lee, M., Kim, M., et al. Incident allergic diseases in post-COVID-19 condition: multinational cohort studies from South Korea, Japan and the UK. Nature Communications. doi: https://doi.org/10.1038/s41467-024-47176-w.
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April 3, 2024