COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long ...COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein-Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.
Metasurfaces are engineered nanostructured interfaces that extend the photonic behavior of natural materials, and they spur many breakthroughs in multiple fields, including quantum optics, ...optoelectronics, and biosensing. Recent advances in metasurface nanofabrication enable precise manipulation of light–matter interactions at subwavelength scales. However, current fabrication methods are costly and time‐consuming and have a small active area with low reproducibility due to limitations in lithography, where sensing nanosized rare biotargets requires a wide active surface area for efficient binding and detection. Here, a plastic‐templated tunable metasurface with a large active area and periodic metal–dielectric layers to excite plasmonic Fano resonance transitions providing multimodal and multiplex sensing of small biotargets, such as proteins and viruses, is introduced. The tunable Fano resonance feature of the metasurface is enabled via chemical etching steps to manage nanoperiodicity of the plastic template decorated with plasmonic layers and surrounding dielectric medium. This metasurface integrated with microfluidics further enhances the light–matter interactions over a wide sensing area, extending data collection from 3D to 4D by tracking real‐time biomolecular binding events. Overall, this work resolves cost‐ and complexity‐related large‐scale fabrication challenges and improves multilayer sensitivity of detection in biosensing applications.
Metasurface fabrication techniques are costly and time‐consuming since multiple complex deposition and patterning steps are required to build a device with a small active area. The digital versatile disk (DVD)‐templated metasurface approach allows the fabrication of a cost‐effective Fano resonant metasurface over a large active area that provides layer‐by‐layer biosensing of binding and interactions of protein, antibody, and virus particles.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Having a Д32 mutation in both cellular copies of the CCR5 gene results in the absence of functional CCR5 protein on the cell surface, and immune cells lacking this protein can resist infection by HIV ...strains that depend on CCR5. Interestingly, when individuals with HIV have received stem-cell transplants to repopulate their immune cells from donors with wild-type copies of the CCR5 gene, HIV is initially undetectable in the patients' bodies, but eventually rebounds if antiretroviral therapy is stopped6-9. By contrast, the standard HIV treatment regimen of one or two pills per day is accompanied by relatively minimal adverse effects; therefore, it is not practical to consider replacing it with a procedure that might risk disease or death, and that creates the need for long-term immunosuppression.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A person infected with HIV who was treated for blood cancer with a stem-cell transplant has gone into viral remission, with no trace of the virus in their blood. A similar outcome in 2009 hadn't been ...replicated until now.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Monitoring the efficacy of novel reservoir-reducing treatments for HIV is challenging. The limited ability to sample and quantify latent infection means that supervised antiretroviral therapy (ART) ...interruption studies are generally required. Here we introduce a set of mathematical and statistical modeling tools to aid in the design and interpretation of ART-interruption trials. We show how the likely size of the remaining reservoir can be updated in real-time as patients continue off treatment, by combining the output of laboratory assays with insights from models of reservoir dynamics and rebound. We design an optimal schedule for viral load sampling during interruption, whereby the frequency of follow-up can be decreased as patients continue off ART without rebound. While this scheme can minimize costs when the chance of rebound between visits is low, we find that the reservoir will be almost completely reseeded before rebound is detected unless sampling occurs at least every two weeks and the most sensitive viral load assays are used. We use simulated data to predict the clinical trial size needed to estimate treatment effects in the face of highly variable patient outcomes and imperfect reservoir assays. Our findings suggest that large numbers of patients-between 40 and 150-will be necessary to reliably estimate the reservoir-reducing potential of a new therapy and to compare this across interventions. As an example, we apply these methods to the two "Boston patients", recipients of allogeneic hematopoietic stem cell transplants who experienced large reductions in latent infection and underwent ART-interruption. We argue that the timing of viral rebound was not particularly surprising given the information available before treatment cessation. Additionally, we show how other clinical data can be used to estimate the relative contribution that remaining HIV+ cells in the recipient versus newly infected cells from the donor made to the residual reservoir that eventually caused rebound. Together, these tools will aid HIV researchers in the evaluating new potentially-curative strategies that target the latent reservoir.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Identifying patients who are at high risk for severe Clostridium difficile-associated disease (CDAD) early in the course of their infection may help clinicians improve outcomes. Therefore, we ...compared clinical features associated with severe versus nonsevere CDAD by retrospectively reviewing records of hospitalized patients whose fecal assays were positive for C. difficile toxin. Of 336 patients, 12.2% had severe disease and 10.1% died from all causes. Regression modeling showed the following to be significantly associated with severe CDAD (p< or =0.05): age >70 years (odds ratio OR 3.35), maximum leukocyte count >20,000 cells/mL (OR 2.77), minimum albumin level <2.5 g/dL (OR 3.44), maximum creatinine level >2 mg/dL (OR 2.47), small bowel obstruction or ileus (OR 3.06), and computed tomography scan showing colorectal inflammation (OR 13.54). These clinical and laboratory markers for severe disease may be useful for identifying patients at risk for serious outcomes or death.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
The biological processes associated with postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) are unknown.
Methods
We measured ...soluble markers of inflammation in a SARS-CoV-2 recovery cohort at early (<90 days) and late (>90 days) timepoints. We defined PASC as the presence of 1 or more coronavirus disease 2019 (COVID-19)–attributed symptoms beyond 90 days. We compared fold-changes in marker values between those with and without PASC using mixed-effects models with terms for PASC and early and late recovery time periods.
Results
During early recovery, those who went on to develop PASC generally had higher levels of cytokine biomarkers including tumor necrosis factor–α (1.14-fold higher mean ratio 95% confidence interval {CI}, 1.01–1.28; P = .028) and interferon-γ–induced protein 10 (1.28-fold higher mean ratio 95% CI, 1.01–1.62; P = .038). Among those with PASC, there was a trend toward higher interleukin 6 levels during early recovery (1.29-fold higher mean ratio 95% CI, .98–1.70; P = .07), which became more pronounced in late recovery (1.44-fold higher mean ratio 95% CI, 1.11–1.86; P < .001). These differences were more pronounced among those with a greater number of PASC symptoms.
Conclusions
Persistent immune activation may be associated with ongoing symptoms following COVID-19. Further characterization of these processes might identify therapeutic targets for those experiencing PASC.
Compared to individuals reporting full recovery, individuals with symptoms for >90 days following COVID-19 had subtle elevations in levels of certain markers of immune activation. Further characterization of these processes might identify therapeutic targets for those experiencing postacute sequelae of SARS-CoV-2tion.
As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be ...identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV,
= 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV,
= 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection. Longitudinal studies to monitor plasma biomarkers and nEV cargo are warranted to assess persistent neurodegeneration and systemic effects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective
As SARS‐CoV‐2 is known to invade neural cell mitochondria, a plasma system for quantifying central nervous system proteins in living humans was used to investigate neuropathogenic ...mechanisms of long‐COVID‐19.
Methods
SARS‐CoV‐2 proteins and mitochondrial proteins (MPs) in enriched plasma neuron‐derived extracellular vesicles (NDEVs) and astrocyte‐derived EVs (ADEVs) were quantified in resolved acute COVID‐19 without post‐acute sequelae of SARS‐CoV‐2 (PASC), PASC without neuropsychiatric manifestations (NP), PASC with NP and healthy controls.
Results
NDEV and ADEV mean levels of SARS‐CoV‐2 S1 and nucleocapsid (N) proteins were higher in all PASC sub‐groups than controls, but only N levels were higher in PASC with than without NP. Exosome marker CD81‐normalized NDEV mean levels of subunit 6 of MP respiratory chain complex I and subunit 10 of complex III, and neuroprotective MPs Humanin and mitochondrial open‐reading frame of the 12S rRNA‐c (MOTS‐c) all were decreased significantly in PASC with NP but not in PASC without NP relative to controls. NDEV levels of MPs voltage‐dependent anion‐selective channel protein 1 (VDAC1) and N‐methyl‐D‐aspartate receptor 1 (NMDAR1) were decreased in PASC without and with NP, whereas those of calcium channel MPs mitochondrial calcium uniporter (MCU), sodium/calcium exchanger (NCLX) and leucine zipper EF‐hand containing transmembrane 1 protein (LETM1) were decreased only in PASC with NP. ADEV levels of MCU and NCLX only were increased in PASC without and with NP.
Interpretation
Abnormal NDEV and ADEV levels of SARS‐CoV‐2 N and S1 protein and MPs correlate with NP and may be biomarkers for long‐COVID prognostics and therapeutic trials. ANN NEUROL 2022;91:772–781
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The current era of COVID-19 is characterized by emerging variants of concern, waning vaccine- and natural infection-induced immunity, debate over the timing and necessity of vaccine boosting, and the ...emergence of post-acute sequelae of SARS-CoV-2 infection. As a result, there is an ongoing need for research to promote understanding of the immunology of both natural infection and prevention, especially as SARS-CoV-2 immunology is a rapidly changing field, with new questions arising as the pandemic continues to grow in complexity. The next phase of COVID-19 immunology research will need focus on clearer characterization of the immune processes defining acute illness, development of a better understanding of the immunologic processes driving protracted symptoms and prolonged recovery (ie, post-acute sequelae of SARS-CoV-2 infection), and a growing focus on the impact of therapeutic and prophylactic interventions on the long-term consequences of SARS-CoV-2 infection. In this review, we address what is known about the long-term immune consequences of SARS-CoV-2 infection and propose how experience studying the translational immunology of other infections might inform the approach to some of the key questions that remain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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