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

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

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

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

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

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

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

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

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

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


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

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

    Source:

    Journal reference:

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

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

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

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

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

    Background

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

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

    About the study

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

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

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

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

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

    Results

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

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

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

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

    Conclusions

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

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

    Journal reference:

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  • Long COVID prevalence varies widely across US states, CDC study finds

    Long COVID prevalence varies widely across US states, CDC study finds

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    In a recent study published in the CDC journal MMWR Morbidity and Mortality Weekly Report, researchers investigated the prevalence of long coronavirus disease 2019 (long COVID) among adults across the United States of America (USA). They found that the prevalence of long COVID varied among the states and territories, ranging from 1.9% in the Virgin Islands to 10.6% in West Virginia.

    otes from the Field: Long COVID Prevalence Among Adults — United States, 2022. Image Credit: Donkeyworx / ShutterstockNotes from the Field: Long COVID Prevalence Among Adults — United States, 2022. Image Credit: Donkeyworx / Shutterstock

    Background

    Long COVID or post-COVID refers to various health issues that persist after acute COVID-19, including neurological and respiratory symptoms, as well as fatigue. About 6.9% of adults in the USA reportedly suffered from long COVID in 2022. However, the current lack of data from states and territories hinders targeted public health responses. The Association of State and Territorial Health Officials and Council of State and Territorial Epidemiologists have also highlighted this gap. The Centers for Disease Control and Prevention (CDC) in the USA conducted a nationwide study to estimate the prevalence of long COVID among adults to address this need.

    About the study

    The CDC utilized data from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) survey of non-institutionalized adults in the USA aged 18 years and older. This cross-sectional, population-based survey employed random digit dialing of phones (cellular and landline) for sampling and gathering information on age, sex, COVID-19 history, and long COVID symptoms lasting at least three months. Prevalence estimates, standardized to the 2020 USA Census Bureau population, were calculated for all adults across states and territories. Weights specific to gender were applied to individuals aged 18–44 years, 45–64 years, and ≥65 years. Analysis was conducted using a Statistical Analysis System (SAS)-callable SUDAAN (short for Survey Data Analysis) while considering the complex survey design.

    Results and discussion

    The national prevalence of long COVID among non-institutionalized adults in the USA was found to be 6.4%, with estimates ranging from 1.9% in the Virgin Islands to 10.6% in West Virginia. Seven states surpassed a prevalence of 8.8%. Variations were observed across regions, with lower prevalence in the Pacific and New England and higher prevalence in the South, West, and Midwest. Limitations of the study include the lack of data on treatment during acute COVID illness, time since illness, symptom duration or severity, and vaccination status in some jurisdictions.

    Conclusion

    In conclusion, the present study fills a crucial gap by providing insights into the prevalence of long COVID, highlighting the need for continued monitoring of state- and territory-level data to inform healthcare planning and policy decisions. The findings highlight the importance of addressing the healthcare needs of individuals with long COVID and identifying geographic disparities to promote health equity through targeted interventions.

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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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  • Wastewater clues could revolutionize Alzheimer’s detection

    Wastewater clues could revolutionize Alzheimer’s detection

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    In a recent review published in the journal Environment International, researchers discuss the benefits of wastewater-based epidemiology (WBE) over conventional diagnostic techniques, the latter of which are often expensive and invasive. They then explore studies in the relatively novel field of biomarker- and peripheral body fluid-based Alzheimer’s disease diagnosis, the potential for integrating these detection approaches in existing WBE platforms, and the challenges currently faced in implementing these integrations.

    Study: Urine biomarkers for AlzheimerStudy: Urine biomarkers for Alzheimer’s disease: A new opportunity for wastewater-based epidemiology? Image Credit: Avigator Fortuner / Shutterstock

    The evolution of Alzheimer’s disease research

    Alzheimer’s disease (AD) is a neurodegenerative condition characterized by the abnormal buildup of proteins (especially amyloid and tau) in and around brain cells, resulting in a progressive cognitive decline. It is a severely debilitating condition, the most common cause of dementia, and the fifth most lethal chronic disease in humans above the age of 65.

    Alarmingly, the global incidence of AD is rising rapidly, with research revealing a more than two-fold increase in less than three decades between 1990 and 2019. Clinical and economic prediction models estimate that by the year 2050, between 114 and 152 million patients will suffer from the disease, with dementia-related financial losses projected to far exceed 2.8 trillion US dollars.

    AD is multifactorial in nature, with a combination of genetic and environmental variables thought to trigger the condition. Unfortunately, this complicates AD diagnoses, with a large portion of cases remaining undetected or detected too late. Conventional diagnostic approaches involve the use of magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. These techniques are expensive and require specialized equipment and expertise, reported to be upwards of 753 euros in Sweden, 649 euros in Germany, and more than 8,400 US dollars in America.

    While less expensive methods of AD diagnoses do exist, they often involve highly invasive surgical procedures. These problems are compounded in low to middle-income countries (LMIC) that often lack the resources required for AD and dementia diagnoses of any kind. Recent AD diagnostic research has focused on using non- or minimally-invasive diagnostic techniques involving biofluids such as blood, urine, and saliva to overcome these challenges. Biomarker concentrations within these biofluids, especially when analyzed using machine learning and other artificial intelligence models, have been shown to be capable of detecting AD long before the emergence of externally observable symptoms, further promoting the adoption of these novel approaches.

    But what if we could go further?

    Following the World Health Organization’s (WHO’s) recommendation for the development of population-level diagnostic and risk-assessment approaches to facilitate better preventive efforts and resource management accompanying its AD response plans, recent studies have investigated the potential of peripheral biofluids, especially urine contents, in AD management.

    Most recently, wastewater-based epidemiology (WBE) is being investigated as a community-scale health monitoring tool utilizing the characterization and quantification of chemicals and biomarkers in sewage water.

    Where are we in WBE implementation?

    Despite WBE first being reported in a more primitive form in 1954 and its current methodology established in 2001, WBE’s implementation remains primarily restricted to the detection of monitoring of pathogenic diseases such as the coronavirus disease 2019 (COVID-19) causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unfortunately, the implementation of WBE in monitoring the bulk of global mortality – chronic, non-communicable diseases (41 million deaths per year representing 74% of annual mortality) – is exceedingly limited.

    Encouragingly, that limited information is promising – thus far, sewage-derived proteomics analyses have identified biomarkers related to cardiovascular disease (CVD), cancers, the presenilin pathway, Huntington’s disease, and potentially even AD. This suggests that the large-scale integration of chronic disease biomarkers into existing WBE platforms could result in substantial savings for human life and the global economy.

    So, why isn’t large-scale implementation happening?

    The population-scale implementation of chronic disease biomarker analyses into WBE infrastructure cannot occur without first overcoming specific challenges. Firstly, we do not know the effects of endogenous biomarker concentrations and their correlations with disease risk. Previous studies have only identified risk-associated biomarkers, not quantify them.

    Secondly, there is a lack of universally validated population parameter markers, let alone in wastewater flows, where (thirdly) the complex matrix of wastewater mixture is expected to render biomarker concentrations extremely low. Current technological limitations may prevent the detection, much less quantification, of a spectrum of biomarkers assessing the community-level risk of multiple diseases.

    What must scientists do to overcome these challenges, at least for AD risk assessments?

    Researchers have identified a number of protein biomarkers associated with AD. These included ones such as AB, Tau, and AD7C-NTP, known to be directly involved in the condition’s pathologic mechanisms, and long noncoding RNAs (LncRNAs) such as BDNF-AS, BACE1-AS, MAGI2-AS3, RMRP, and EBF3-AS. LncRNAs are a fascinating class of large RNA molecules that serve epigenetic functions despite not coding for any functional proteins.

    Implementing mechanisms to measure oxidative stress and neurotransmitter dysregulations could serve as validatory evidence in the risk assessment of AD and many other diseases.

    “…advanced analytical techniques that have proven successful in clinical settings have been suggested as solutions to these challenges, including ultra-performance liquid chromatography coupled with a hybrid quadrupole orthogonal time-of-flight mass spectrometer (UPLC-Q-TOF/MS/MS), capillary electrophoresis time-of-flight mass spectrometry (CE-TOF-MS), microfluidics-based separation methods, SIMOA or antibody or aptamer-based biosensors.”

    Journal reference:

    • Armenta-Castro, A., Núñez-Soto, M. T., Rodriguez-Aguillón, K. O., Aguayo-Acosta, A., Oyervides-Muñoz, M. A., Snyder, S. A., Barceló, D., Saththasivam, J., Lawler, J., Sosa-Hernández, J. E., & Parra-Saldívar, R. (2024). Urine biomarkers for Alzheimer’s disease: A new opportunity for wastewater-based epidemiology? Environment International, 184, 108462, DOI – 10.1016/j.envint.2024.108462, https://www.sciencedirect.com/science/article/pii/S0160412024000485

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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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  • 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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  • Trial investigates efficacy of online supervised group mental and physical rehabilitation program for long COVID patients

    Trial investigates efficacy of online supervised group mental and physical rehabilitation program for long COVID patients

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    In a recent study published in the BMJ, researchers evaluated the efficacy of an online supervised group mental and physical rehabilitation program in adults with long COVID.

    Study: Clinical effectiveness of an online supervised group physical and mental health rehabilitation programme for adults with post-covid-19 condition (REGAIN study): multicentre randomised controlled trial. Image Credit: Dmitry Demidovich/Shutterstock.com
    Study: Clinical effectiveness of an online supervised group physical and mental health rehabilitation programme for adults with post-covid-19 condition (REGAIN study): multicentre randomised controlled trial. Image Credit: Dmitry Demidovich/Shutterstock.com

    Background

    Over 17 million people in the European region of the World Health Organization (WHO) may have experienced coronavirus disease 2019 (COVID-19) symptoms longer than four weeks. Common symptoms of this multisystem condition, known as long COVID or post-COVID-19 condition, include muscle aches, fatigue, dyspnea, and cognitive dysfunction that can profoundly impact quality of life, societal participation, and economic productivity. The pathophysiology of long COVID has not been fully characterized.

    As such, current medical management and treatments have limited efficacy. The biopsychosocial care model may improve outcomes for long COVID patients. Multicomponent mental and physical rehabilitation could improve fatigue, quality of life, and breathlessness. So far, few quasi-experimental studies evaluated exercise-based interventions for individuals with long COVID, with no definitive, high-quality evidence.

    About the study

    In the present study, researchers evaluated the clinical effectiveness of a group rehabilitation program for people with long COVID. The rehabilitation exercise and psychological support after COVID-19 infection (REGAIN) was a multi-center, parallel-group, pragmatic, randomized controlled trial. Participants were recruited in England and Wales. Adults (26-86 years) discharged at least three months after hospitalization with COVID-19 who had ongoing mental and physical sequelae were recruited.

    Subjects were excluded if they had severe mental health problems, contraindications to exercise training, or were enrolled in other rehabilitation programs. A baseline questionnaire was administered before randomization to REGAIN or usual care. Usual care participants received the best practice usual care; this involved an online consultation with a trained practitioner, wherein generic advice was provided on recovery and physical activity.

    The REGAIN intervention was an eight-week, supervised, home-based, group rehabilitation program, providing online consultation with a REGAIN practitioner. REGAIN participants joined weekly live online group exercise and psychological support sessions. Equipment-free, supervised, personalized exercise sessions were delivered in online groups to improve fatigue, cardiovascular fitness, balance, and strength and restore confidence in daily living activities.

    Psychological support sessions were aimed at augmenting psychological capability and increasing COVID-19-related knowledge and its impact on everyday life. The primary outcome of the study was health-related quality of life, determined using the patient-reported outcomes measurement information system (PROMIS). Secondary outcomes included dyspnea, cognitive function, physical activity, anxiety, depression, and general health, among others. Outcomes were assessed at three, six, and 12 months.

    Findings

    Of over 39,000 people invited to participate between January 2021 and July 2022, 1,043 expressed interest. Following exclusions, 298 and 287 subjects were randomized to REGAIN and usual care, respectively. Most participants were female (52%), White (88%), and obese/overweight (88%). One-third of participants required intensive care during COVID-19 hospitalization.

    The average time from discharge to randomization was 323 days. The baseline health-related quality of life was low; around 40% had low physical activity. More than a third of participants could not work due to long COVID. Primary outcome data were available for 80% of REGAIN and 86% of usual care participants. The health-related quality of life improved more for REGAIN participants than usual care recipients at three months.

    There was a significant group difference in health-related quality of life, primarily driven by three PROMIS sub-scores – fatigue, depression, and pain interference. While the effect of the intervention was not evident at six months, it was sustained at 12 months. REGAIN participants had increased odds of being more physically active than usual care recipients. At three months, 7% more REGAIN subjects met the physical activity guideline (> 150 minutes of moderate-intensity activity per week).

    Furthermore, more REGAIN participants reported feeling much better compared to three months than usual care subjects. Adverse events were reported in both groups. Most serious adverse events were related to hospitalization or extended stay at the hospital. Two adverse events were related to the REGAIN intervention. One serious adverse event was possibly related to the intervention. Post-exertional exacerbation of symptoms was not observed.

    Conclusions

    In sum, the REGAIN intervention was clinically effective in improving health-related quality of life for adults with post-COVID-19 condition compared to usual care at three months post-randomization. This effect was mainly due to improvements in pain interference, fatigue, and depression. Moreover, the effect was sustained at 12 months. In both groups, there were improvements in the overall quality of life and other well-being indices.

    Journal reference:

    • Gordon McGregor, Harbinder Sandhu, Julie Bruce, et al. Clinical effectiveness of an online supervised group physical and mental health rehabilitation programme for adults with post-covid-19 condition (REGAIN study): multicentre randomised controlled trial. BMJ, 2024. doi: 10.1136/bmj-2023-076506
      https://www.bmj.com/content/384/bmj-2023-076506
       

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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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