COVID-19

Posted on A to Z of Medical Conditions, Infectious Diseases

Vagus nerve stimulation – an electric pill for inflammation?

aVNS


Individualised auricular vagus nerve stimulation at the right time and with the right strength. CREDIT TU Wien

A system out of balance

When a virus – such as SARS-CoV-2 – triggers an inflammatory response in the body, this information is transmitted to the brain via the sensory nervous system. The Vagus nerve, which extends from the brain to most organs in the human body, responds in a regulatory way with an anti-inflammatory reflex. However, if the anti-inflammatory response is too weak, an excessive inflammation may negatively affect the body’s own regeneration. To restore the balance between the initially protective inflammatory response and the regenerative processes, aVNS systems can be used.

To test their hypothesis that aVNS also supports the healing process in severe Covid-19 cases, TU researchers worked closely with the Hospital Favoriten, the Medical University of Vienna, the Health Service Centre of the Vienna Private Clinic, the Sigmund Freud Private University Vienna and the Immunological Day Clinic Vienna.

aVNS in severe Corona courses

In its most recent study, the research team was able to show that the positive effect that Vagus nerve stimulation has on the course of severe Corona diseases, which was already predicted in 2020 – at the beginning of the pandemic – actually exists. For this purpose, the team investigated the use of aVNS on patients who were acutely ill with Corona and were about to receive artificial respiration.

When the virus attacks the body, the inflammatory response and healing process can become unbalanced. The inflammatory response of the body then causes more damage than the virus itself. This balance must be restored – for example, by using an aVNS system. “The electrostimulation of the auricular vagus nerve was not only able to stop the inflammatory reaction in Covid-19 patients, it was even able to counteract it,” Eugenijus Kaniusas, professor at the Institute for Biomedical Electronics at TU Wien, emphasises the result.

Stimulating at the exact right time

The therapeutic success of aVNS also increases by adapting the system. If an aVNS system constantly sends electrical impulses, this can lead to side effects such as pain. The power consumption is also significantly higher compared to when the system reacts individually to the patient and sends targeted stimuli. To realise this, the researchers around PhD student Babak Dabiri have integrated a closed-loop control. Eugenijus Kaniusas explains: “This allows us to stimulate the Vagus nerve exactly when the brain is listening. This is the case when the heart is contracting and blood is flowing into the vessels or when the person is exhaling.” In this way, over- and under-stimulation can be prevented, which often results from persistent aVNS.

While simple measurements refer exclusively to the past, Kaniusas and his team worked with predictions: “In the study, we were able to show that predictive stimulation works and leads to the desired result. This was possible due to a feedback function of the system, via which the aVNS system can constructively interfere with the parasympathetic system,” the electrical engineer Kaniusas says. “The aVNS system listens to the measured biosignals and sends its stimulus at exactly the right time, like an intelligent electric pill,” he finally draws a comparison. This is an important step in the direction of personalisation, through which the research team also expects better therapeutic success and more acceptance by users.

Posted on Infectious Diseases

Effective oxygen treatment is now available for millions suffering from long-term COVID-19 symptoms

Improved cerebral blood flow by HBOT in patient suffering from post-COVID symptoms.


Improved cerebral blood flow by HBOT in patients suffering from post-COVID symptoms. CREDIT Sagol center for hyperbaric medicine.

  • Researchers from Tel Aviv University exposed patients with long-term COVID-19 symptoms to intensive Hyperbaric Oxygen Therapy (HBOT) treatment, and found significant improvement in cognitive, neurological, and psychiatric functions.
  • The treatments were accompanied by advanced MRI imaging of the patients’ brains, identifying damage from the COVID-19 virus, and correlating the images with clinical findings, before and after HBOT treatment.

A groundbreaking new study from Tel Aviv University, the first of its kind in the world, found a promising treatment for long-term COVID-19 symptoms, based on advanced Hyperbaric Oxygen Therapy (HBOT). Long COVID, which affects up to 30% of patients infected by the COVID-19 virus, is characterized by a range of debilitating cognitive symptoms such as inability to concentrate, brain fog, forgetfulness and difficulty recalling words or thoughts – persisting for more than three months, and sometimes up to two years. To date, no effective therapy has been suggested, leaving many millions of sufferers around the world with no remedy. The researchers: “Our study is the first randomized controlled trial to demonstrate a real solution for long COVID. Patients exposed to an intensive protocol of HBOT treatments showed significant improvement compared to the control group. For millions suffering from long-term COVID-19 symptoms, the study provides new hope for recovery.”

The study was conducted by the Sagol Center for Hyperbaric Medicine and Research at Tel Aviv University and Shamir Medical Center (Assaf Harofeh).It was led by Prof. Shai Efrati, Director of the Sagol Center and a faculty member at TAU’s Sackler School of Medicine and Sagol School of Neuroscience, and by Dr. Shani-Itskovich Zilberman from the Sagol Center for Hyperbaric Medicine and TAU’s Sackler School of Medicine. Other chief contributors were Dr. Merav Catalogna, lead data scientist from the Shamir Medical Center (Assaf Harofeh) and Dr. Amir Hadanny from the Sagol Center and TAU’s Sackler School of Medicine. The paper was published in Scientific Reports.

Prof. Efrati explains: “Today we understand that in some patients, the COVID-19 virus penetrates the brain through the cribriform plate, the part of the skull located just above our nose, and triggers chronic brain injury – mainly in brain regions in the frontal lobe, responsible for cognitive function, mental status and pain interpretation. Consequently, affected patients experience a long-term cognitive decline, with symptoms such as brain fog, loss of concentration and mental fatigue.  In addition, since the frontal lobe is damaged patients may suffer from mood disturbance, depression, and anxiety. These clinical symptoms, identified in patients all over the world, were corroborated by the World Health Organization in an official definition of so-called “long COVID” issued in October 2021, including cognitive dysfunction as one of the common symptoms. A recent study from the Universities of Cambridge and Exeter reported that 78% of long-term COVID-19 patients experienced difficulties with concentration, 69% reported brain fog, and 68% reported forgetfulness. Thus, long-term COVID-19 effects can be very detrimental to the sufferer’s quality of life, and no effective treatment has yet been found. In our study we harnessed HBOT, already proven effective in the treatment of other forms of brain injury (such as stroke, trauma, age-related cognitive decline and treatment-resistant PTSD), to the global effort to find a solution for long COVID-19.”

The study, designed as a prospective, randomized, double-blind, placebo-controlled clinical trial, included 73 patients with reported post-COVID-19 cognitive symptoms such as inability to concentrate, brain fog, forgetfulness and difficulty recalling words or thoughts, persisting for more than three months following an RT-PCR test confirming COVID-19 infection.

Participants were divided into two groups: 37 patients received HBOT treatment, while 36 patients served as a sham-controlled group, receiving placebo treatment. Both patients and investigators were unaware of their designated treatment protocol. The unique protocol consisted of 40 daily HBOT sessions, five sessions per week within a two-month period, in which patients entered a multi-place HBOT chamber and breathed 100% oxygen by mask at 2 atmospheres absolute (ATA) for 90 minutes with oxygen fluctuations. The control group received placebo treatment, breathing normal air.

In addition, all participants underwent a computerized cognitive test, as well as advanced high-resolution brain imaging (profusion MRI and DTI) at two points in time – when entering the trial and after its completion.

The results were highly encouraging: patients treated with HBOT showed significant improvement, while in the control group long COVID symptoms remained largely unchanged. In HBOT-treated patients, the greatest improvements were exhibited in the global cognitive function, attention, and executive functions (the capacity to plan, organize, initiate, self-monitor and control one’s responses in order to achieve a goal). Other benefits included better information processing speed, improved psychiatric symptoms, more mental energy, better sleep quality, and less body pain. All clinical findings were correlated with the participants’ brain images, indicating significant change in the parts of the brain related to each function, which had been visibly damaged by the COVID-19 virus.

Dr. Shani-Itskovich Zilberman: “We know that HBOT repairs brain damage through a process of regeneration – generating new neurons and blood vessels. We believe that the beneficial effects of the unique treatment protocol in this study can be attributed to renewed neuroplasticity and increased brain perfusion in regions associated with cognitive and emotional roles.”

Prof. Efrati: “For the first time, our study proposes an effective treatment for the debilitating long COVID syndrome, repairing brain injury with an intensive protocol of HBOT. Moreover, the study reveals the very real biological damage to brain tissues induced by the COVID-19 virus, and how repairing this damage reduces symptoms and can eventually lead to recovery. From a broader perspective, these findings can also suggest that other neurological and psychiatric syndromes might be triggered by biological agents such as viruses, opening new possibilities for future treatments.” 

Posted on Infectious Diseases

New antibody detection method for coronavirus that does not require a blood sample

New antibody detection method for coronavirus that does not require a blood sample

Researchers report a new, minimally invasive, antibody-based detection method for SARS-CoV-2 that could lead to the blood sample-free detection of many diseases CREDIT Institute of Industrial Science, The University of Tokyo

Despite significant and stunning advances in vaccine technology, the COVID-19 global pandemic is not over. A key challenge in limiting the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is identifying infected individuals. Now, investigators from Japan have developed a new antibody-based method for the rapid and reliable detection of SARS-CoV-2 that does not require a blood sample.

The ineffective identification of SARS-CoV-2-infected individuals has severely limited the global response to the COVID-19 pandemic, and the high rate of asymptomatic infections (16%–38%) has exacerbated this situation. The predominant detection method to date collects samples by swabbing the nose and throat. However, the application of this method is limited by its long detection time (4–6 hours), high cost, and requirement for specialized equipment and medical personnel, particularly in resource-limited countries.

An alternative and complementary method for the confirmation of COVID-19 infection involves the detection of SARS-CoV-2-specific antibodies. Testing strips based on gold nanoparticles are currently in widespread use for point-of-care testing in many countries. They produce sensitive and reliable results within 10–20 minutes, but they require blood samples collected via a finger prick using a lancing device. This is painful and increases the risk of infection or cross-contamination, and the used kit components present a potential biohazard risk. 

Lead author Leilei Bao from the Institute of Industrial Science, The University of Tokyo, explains: “To develop a minimally invasive detection assay that would avoid these drawbacks, we explored the idea of sampling and testing the interstitial fluid (ISF), which is located in the epidermis and dermis layers of human skin. Although the antibody levels in the ISF are approximately15%–25% of those in blood, it was still feasible that anti-SARS-CoV-2 IgM/IgG antibodies could be detected and that ISF could act as a direct substitute for blood sampling.”

After demonstrating that ISF could be suitable for antibody detection, the researchers developed an innovative approach to both sample and test the ISF. “First, we developed biodegradable porous microneedles made of polylactic acid that draws up the ISF from human skin,” explains Beomjoon Kim, senior author. “Then, we constructed a paper-based immunoassay biosensor for the detection of SARS-CoV-2-specific antibodies.” By integrating these two elements, the researchers created a compact patch capable of on-site detection of the antibodies within 3 minutes (result from in vitro tests).

This novel detection device has great potential for the rapid screening of COVID-19 and many other infectious diseases that is safe and acceptable to patients. It holds promise for use in many countries regardless of their wealth, which is a key aim for the global management of infectious disease. 

Posted on Diabetes, Infectious Diseases

The surprising link between SARS-CoV-2 infection and new-onset diabetes

Researchers from Osaka University find that infection with SARS-CoV-2 activates the IRF1 gene and impairs insulin/IGF signalling in the lung, liver, adipose tissue, and pancreatic cells

Fig. Pathogenesis of COVID-19 symptoms and therapeutic strategies.


The insulin/IGF signalling pathway plays an important role in many biological processes, such as energy metabolism and cell survival. SARS-CoV-2 infection impairs transcriptional expression of the insulin/IGF signalling pathway in the host lung, liver adipose tissue, and pancreatic cells, which is likely attributed to interferon regulatory factor 1 (IRF1). The pathological trait is aggravated in whole blood, a systemic indicator, of critical patients with COVID-19 with exacerbated cell damage, cell death, and metabolic abnormalities, which could be ameliorated by androgen (DHT) and/or glucocorticoid (DEX) interventions. Higher basal IRF1 expression by pathological (older age, male sex, obesity, and diabetes) reasons in respiratory, metabolic, and/or endocrine organs might contribute to synergistic upregulation of IRF1 in response to SARS-CoV-2 infection, which may make the people more vulnerable to COVID-19. CREDIT©2022 Jihoon Shin., SARS-CoV-2 infection impairs the insulin/IGF signalling pathway in the lung,

– It has become abundantly clear that coronavirus disease 19 (COVID-19), despite being transmitted by breathing in the SARS-CoV-2 virus, can have harmful effects far beyond the lungs. Now, researchers from Japan have identified a pivotal gene that mediates the effects of SARS-CoV-2 infection on blood sugar metabolism.

In a study published in June in Metabolism, researchers from Osaka University reveal that COVID-19 can cause metabolism problems, and sometimes even diabetes, by interfering with insulin signaling.

COVID-19 is best known for causing respiratory disease, but can also damage other organ systems; notably, disruption of blood sugar regulation can lead to new-onset diabetes. However, it is unclear how infection with the SARS-CoV-2 virus results in these effects.

“The insulin/IGF signaling pathway is a key pathway in the regulation of energy metabolism and cell survival,” says Jihoon Shin, first author on the study. “Therefore, we suspected that SARS-CoV-2 affects this signaling pathway to cause problems with blood sugar regulation.”

To test this, the researchers analyzed datasets of gene expression from patients, as well as in vivo and in vitro models, infected with SARS-CoV-2. They specifically looked for genes that were noticeably over- or under-expressed compared with uninfected patients, animals, or cells.

“The results were striking,” states Iichiro Shimomura, senior author of the study. “Infection with SARS-CoV-2 affected the expression of insulin/IGF signaling pathway components in the lung, liver, adipose tissue, and pancreatic cells. Moreover, these changes were attributed in part to activation of interferon regulatory factor 1 (IRF1).”

Further investigation showed that IRF1 expression is elevated in older patients, men, obese individuals, and patients with diabetes. The synergistic effect of older age, male sex, obesity and diabetes with SARS-CoV-2 means that the expression of IRF1 occurs at an increased rate, which may explain why these patients are more vulnerable to COVID-19. In addition, critical patients with COVID-19 had higher IRF1 expression and lower insulin/IGF signaling pathway genes in their blood compared with noncritical patients. Finally, treating SARS-CoV-2–infected cells or an animal model with hormonal factors that decreased IRF1 expression enhanced insulin/IGF signaling.

“Our findings suggest that SARS-CoV-2 infection impairs insulin/IGF signaling by increasing IRF1 expression, thereby disrupting blood sugar metabolism. Decreasing IRF1 expression by treatment with factors such as dihydrotestosterone and dexamethasone could help mitigate the effects of COVID-19,” says Shin.

Given the devastating impact that COVID-19 can have on multiple organ systems, treatment strategies that could decrease the effect of the disease on blood sugar metabolism could be vitally important. By identifying patients at greater risk of experiencing these effects and intervening to decrease IRF1 activation, some of the severe consequences of COVID-19 could be avoided in susceptible populations.

Posted on Rheumatoid arthritis

Higher rate of COVID-19 death before vaccination linked to certain common inflammatory immune conditions

People with certain inflammatory immune conditions affecting the joints, bowel and skin, such as rheumatoid arthritis, may have been more at risk of dying or needing hospital care if they got COVID-19 before vaccination compared with the general population, according to a new study published in The Lancet Rheumatology.

The findings are based on analysis of 17 million patient GP records in England during the first phase of the pandemic from March-September 2020, when the UK was in lockdown and before vaccines were available. Since then, many of the people treated with medicines analysed in this study have been specifically targeted for third primary vaccine doses followed by boosters and are on a list of people to offered anti-viral treatments.

The study was conducted by a team from the London School of Hygiene & Tropical Medicine (LSHTM) using the OpenSAFELY platform with colleagues from the St John’s Institute of Dermatology at Guy’s and St Thomas’ NHS Foundation Trust, University of Oxford, King’s College London, the University of Exeter and the University of Edinburgh.

More than one million patients in the analysis had immune-mediated inflammatory diseases (IMIDs). These included inflammatory bowel disease such as Crohn’s disease and ulcerative colitis, conditions affecting the joints such as rheumatoid arthritis, and skin conditions including psoriasis.

After accounting for age, sex, deprivation, and smoking status, the research suggests that people with IMIDs affecting the bowel, joints and skin had a 23% increased risk of COVID-19-related death and 23% increased risk of COVID-related hospitalisation compared to people without IMIDs before the introduction of vaccines and anti-viral treatments. People with inflammatory joint disease appeared to be at greatest risk compared to those with gut or skin disease. Compared to the general population, the risk of death was estimated by the researchers to be approximately eight extra deaths per 1,000 people with joint disease in a year (without taking into account other differences between people with and without joint disease, e.g. age and other health conditions).

Study author Professor Sinéad Langan, Wellcome Senior Clinical Fellow and Professor of Clinical Epidemiology at LSHTM, said: “During the height of the pandemic in England in 2020, many people with inflammatory conditions affecting the bowel, joints and skin were advised to stay at home and shield because doctors did not know how COVID-19 would affect them, or what the effects of drugs such as immune modifying therapies used to treat IMIDs would be.

“Our study provides the most accurate assessment of risk of severe COVID-19 before vaccination in people with IMIDs and with the drugs used for their treatment. We hope this analysis will help to inform evidence-based policy as we continue to live with COVID-19.”

The team also investigated the impact of certain medication, identifying around 200,000 people who were on immune modifying drugs. The study found there was no overall increased risk of COVID-19 death or hospitalisation for patients on most targeted immune modifying drugs (often referred to as biologics) compared to standard systemics (that work on the wider immune system) given to treat this group of conditions. For example, there was no increase in severe COVID-19 infections (death, critical care admission or death, or hospitalisation) in people taking most of the targeted immune modifying therapies examined — including TNF blockers such as adalimumab — compared to more commonly used standard immune suppressants such as methotrexate.

Professor Catherine Smith, consultant dermatologist at St John’s Institute of Dermatology at Guy’s and St Thomas’ NHS Foundation Trust, said: “We know that certain factors, such as being older, increase a person’s risk of suffering severe COVID-19 infection. But until now we did not know whether severe COVID-19 risk increases with ongoing health conditions related to problems with the immune system such as arthritis, Crohn’s disease and psoriasis.

“Our study provides important information that will help guide policymakers to ensure prevention strategies such as vaccination, and early intervention treatments such as anti-virals are targeted towards those most at risk. 

“Overall our findings with respect to immune-modifying drugs are reassuring. It’s important that people continue to take prescribed medication and discuss treatment decisions with their physicians and getting vaccines according to recommendations.”

The OpenSAFELY platform accesses an unprecedented scale of data accessed through a Trusted Research Environment to preserve an individual’s privacy. It provides the full dataset of all raw, single-event-level clinical events for all individuals at 40% of all GP practices in England, including all tests, treatments, diagnoses, and clinical and demographic information linked to various sources of hospital data including, for the first time, a comprehensive dataset of medications supplied by hospitals.

This study was made possible through OpenSAFELY links to a new source of data with information on “high cost” drugs. Due to the way these specialist drugs are prescribed, for example through schemes via home care companies, this means they are not usually on GP records. The study marks the first time researchers have been able to analyse this group of drugs in this way, and highlights why access to these data is critical for research.

Co-author Dr Nick Kennedy, Consultant Gastroenterologist and Clinical Senior Lecturer at the University of Exeter, said: “Our study is an example of the high quality, collaborative research that has taken place during the pandemic using OpenSafely’s innovative research platform. For patients with inflammatory bowel disease, the overall message is reassuring, although there was some increase in the risk of being hospitalised in those who had COVID-19.

“Our research also shows that the targeted drugs we commonly use to treat Crohn’s and colitis are not associated with increased risk of poor outcomes.”

The authors acknowledge limitations of the study including the fact that people with these conditions may have shielded or avoided infection with COVID-19 and that other health issues such as cardiovascular disease and diabetes may affect COVID-19 outcomes for people with IMIDs, as well as the potential for misclassification of prescriptions or medication on the patient records.