Omicron Significantly Different From Other Variants

Within only three weeks after the omicron variant was first identified in Houston Methodist patients, this variant rapidly took over and became the cause of a majority of new cases. By contrast, the delta variant took about three months to reach that same milestone after initial detection. Causing 98% of all new COVID-19 cases by the beginning of 2022, omicron had infected 4,468 of Houston Methodist’s patients by Jan. 5.

Houston Methodist physician-scientists found omicron patients are significantly younger, have increased vaccine breakthrough rates and are less likely to be hospitalized than patients with COVID-19 caused by the alpha or delta variants. Consistent with this decreased disease severity, patients infected with the omicron variant of COVID-19 required less intensive respiratory support and had shorter hospital stays (Am J Path 2022 Feb 3. doi:10.1016/j.ajpath.2022.01.007).

 

Compared with Houston Methodist patients infected with alpha or delta variants, the median age of omicron patients was 44.3 years versus 50 for alpha and 48.3 for delta; hospital length of stay was 3.2 days for omicron, 5.1 days for alpha and 5.4 days for delta; and omicron resulted in 55.4% of breakthrough cases in vaccinated patients, whereas 5.4% and 0.9% of vaccinated patients were infected with the alpha and delta variants, respectively.

As of mid-January, the researchers had also identified three patients with the BA.2 “stealth omicron” variant, which requires whole-genome sequencing to distinguish it from delta and the original BA.1 omicron strain. These were the first three “stealth omicron” cases discovered in Texas.

Houston Methodist has one of the largest, most comprehensive SARS-CoV-2 virus genome sequencing studies in the country, analyzing the genome of every positive COVID-19 sample identified throughout Houston Methodist’s hospital system. To get ahead of the virus and detect mutations that affect patient outcomes, such as causing more severe disease or impeding effectiveness of treatments and vaccines, Houston Methodist has sequenced nearly 80,000 SARS-CoV-2 virus genomes since the beginning of the pandemic.

Why Does COVID-19 Affect a Person’s Sense of Smell?

Infection with SARS-CoV-2 indirectly dials down the action of olfactory receptors, proteins on the surfaces of nerve cells in the nose that detect odors, leading to olfactory dysfunction (Cell 2022 Jan 26. doi:10.1016/j.cell.2022.01.024).

In most cases, the dysfunction lasts only a few weeks, but for more than 12% of COVID-19 patients, olfactory dysfunction persists in the form of ongoing reduction in hyposmia or changes in parosmia.

Led by researchers from NYU Grossman School of Medicine and Columbia University, the new study may also shed light on the effects of COVID-19 on other types of brain cells, and other lingering neurologic effects of COVID-19 like brain fog, headaches and depression.

Experiments showed the presence of the virus near neurons in olfactory tissue brought an inrushing of immune cells, microglia and T cells, which release cytokines that change the genetic activity of olfactory nerve cells, even though the virus does not infect them, the researchers said. Where immune cell activity would dissipate quickly in other scenarios, in the brain, immune signaling appears to persist in a way that reduces the activity of genes needed for the building of olfactory receptors.

To gain insight into COVID-19?induced loss of sense of smell, the researchers explored the molecular consequences of SARS-CoV-2 infection in golden hamsters and in olfactory tissue taken from 23 human autopsies. 

They confirmed that SARS-CoV-2 infection, and the immune reaction to it, decreases the ability of DNA chains in chromosomes that influence the formation of olfactory receptor building to be open and active, and to loop around to activate gene expression. In both hamster and human olfactory neuronal tissue, the team detected persistent and widespread downregulation of olfactory receptor building. Other work posted by the authors suggests that olfactory neurons are wired into sensitive brain regions, and that ongoing immune cell reactions in the nasal cavity could influence emotions and cognition consistent with long COVID.

Experiments in hamsters recorded over time revealed that downregulation of olfactory neuron receptors persisted after short-term changes that might affect the sense of smell had naturally recovered. This suggests COVID-19 causes longer-lasting disruption in chromosomal regulation of gene expression, representing a form of “nuclear memory” that could prevent the restoration of olfactory receptor transcription even after SARS-CoV-2 is cleared, they said.

“The realization that the sense of smell relies on ‘fragile’ genomic interactions between chromosomes has important implications,” said co-corresponding author Benjamin tenOever, PhD, a professor in the Department of Microbiology at NYU Langone Health, in New York City. 

“If olfactory gene expression ceases every time the immune system responds in certain ways that disrupts interchromosomal contacts, then the lost sense of smell may act as the ‘canary in the coal mine,’ providing any early signals that the COVID-19 virus is damaging brain tissue before other symptoms present, and suggesting new ways to treat it.”

How a SARS-CoV-2 infection Can Become Severe COVID-19

Severe courses of COVID-19 are marked not only by strong immune activation and inflammatory reactions, but also by a dysfunctional endothelium. If this barrier between blood flow and tissue is damaged, the patient’s condition deteriorates (Signal Transduct Target Ther 2021 Dec 10. doi:10.1038/s41392-021-00819-6).

Many clinical symptoms, such as the destruction of blood vessels in the lungs and acute respiratory distress syndrome, pointed to an impact on the endothelium, according to Christine Falk, PhD, a scientist at the Hanover Medical School and the German Center for Infection Research.

The endothelium is a thin layer of cells that line blood vessels, forming a barrier between blood flow and the surrounding tissues. Infection with SARS-CoV-2 appears to cause strong activation of immune and endothelial cells in the lungs, resulting in the release of various soluble plasma proteins. Severe COVID-19 cases are associated with a dysfunction of the endothelium wherein the barrier between the alveoli and the surrounding vessels is no longer intact.

The scientists studied 25 patients with severe COVID-19 and 17 recovered patients in the ICU. They found the severity of the disease is linked to disruption of the endothelial barrier and can be measured by looking at inflammatory and endothelial plasma proteins. A pattern of seven plasma proteins appears to be associated with a severe form of the disease, which is characterized by strong inflammatory processes and in which the endothelium is permanently damaged. Furthermore, recovery from severe COVID-19 seems to be related to the regeneration of this endothelial barrier.

The investigators found excessive activation of T-lymphocytes and natural killer cells as well as development of memory T-cells and strong proliferation of plasmablasts, which are cells that can produce large amounts of antibodies. Furthermore, ICU patients infected with SARS-CoV-2 had high titers of spike- and nucleocapsid-specific antibodies. 

The researchers found particularly interesting that the immune cell phenotype of these patients mainly changed over time and was less related to progressive severity of the disease. In contrast, the progression of COVID-19 was closely linked to increased levels of various soluble plasma proteins, namely certain inflammatory mediators and especially endothelial factors.

“We were able to demonstrate that ICU patients with COVID-19 can be divided into different groups based on their plasma protein profile, which are associated with disease severity,” explained lead author Louisa Ruhl, a PhD doctoral student at the Hanover Medical School. This could be a potential biomarker for severe COVID-19 courses, they said.  

COVID-19 Vaccination Protects Against Severe Disease Outcomes

Severe COVID-19 outcomes are rare among adults who have been vaccinated against SARS-CoV-2, according to data from 465 facilities (MMWR Morb Mortal Wkly Rep 2022;71[1]:19-25).

A total of 1,228,664 people who completed their primary vaccination series during December 2020 through October 2021 were included in the analysis. Severe disease outcomes were identified as diagnosis of acute respiratory failure, need for noninvasive ventilation, ICU admission or death.

After vaccination, 2,246 people contracted COVID-19, a rate of 18 per 10,000. Of these, 327 were hospitalized, 189 had a severe COVID-19 outcome, and 36 had a COVID-19–related death. All people who developed severe COVID-19 outcomes after vaccination had at least one of eight risk factors: age at least 65 years, being immunocompromised, diabetes mellitus, pulmonary disease, liver disease, chronic kidney disease, neurologic disease and cardiac disease.

“Our study confirms that vaccines are effective in lowering the risk of severe COVID-19,” said Christina Yek, MD, a clinical fellow in the Critical Care Medicine Department of the National Institutes of Health.

“These findings are also critical to help identify persons at continued risk of severe outcomes despite vaccination, who may benefit from targeted interventions including chronic disease management, exposure reduction, additional primary and booster vaccine doses, and effective pharmaceutical therapy, to reduce the risk for severe COVID-19 outcomes,” she added.

The study authors said the findings confirm the overwhelming benefit of COVID-19 vaccination and increasing COVID-19 vaccination coverage is a public health priority.

“Future studies,” Dr. Yek added, “should use contemporary data to describe risk factors for severe disease with the SARS-CoV-2 omicron variant and after booster vaccination.”

This Is Your Brain on COVID-19

The heart is not the only organ affected by COVID-19. A study from researchers at Columbia University Vagelos College of Physicians and Surgeons reports that the brains of a small sample of patients who died of COVID-19 display some of the same molecular changes found in the brains of people with Alzheimer's disease.

The findings could help explain the memory problems reported by sufferers of long COVID, although the researchers caution that the study is small—with data from only 10 patients—and needs to be replicated by others (Alzheimers Dement 2022 Feb 3. doi:10.1002/alz.12558)

Early reports of “brain fog” and persistent cardiac symptoms in COVID-19 survivors prompted the Columbia researchers to investigate how certain molecules, called ryanodine receptors, were affected by the disease.
Defective ryanodine receptors have been implicated in diverse pathogenic processes, ranging from heart and lung disease to the brain's response to stress and Alzheimer's disease, as reported in research led by Andrew Marks, MD, the chair of the Department of Physiology and Cellular Biophysics at the Vagelos College of Physicians and Surgeons, in New York City.

“What we found is really, I think, quite unexpected: Not only did we find defective ryanodine receptors in the hearts and lungs of deceased COVID patients, we also found them in their brains,” Dr. Marks said.

Inside neurons, defective ryanodine receptors have previously been linked to an increase in phosphorylated tau, a well-known hallmark protein of Alzheimer's.

In the new study, the Columbia researchers found high levels of phosphorylated tau in the brains of the COVID patients in addition to defective ryanodine receptors.

Phosphorylated tau was found in both areas where tau is typically located in Alzheimer's patientsand where it is not typically located in those patients. That suggests phosphorylated tau in the COVID-19 patients could be a sign of early-stage Alzheimer's and also contribute to other neurologic symptoms observed in COVID patients.

Increased levels of phosphorylated tau in the brain are believed to be associated with memory problems in Alzheimer's and could be causing similar issues in people with long COVID, Dr. Marks said.

Based on the findings, together with additional changes found in the brain, the investigators theorized that the immune response characteristic of severe COVID causes inflammation in the brain, which in turn leads to dysfunctional ryanodine receptors and then increases in phosphorylated tau. No changes in the pathways that lead to the formation of amyloid beta—another hallmark of Alzheimer's—were found. And perhaps, memory and neurologic impairments in long COVID can be traced to defective ryanodine receptors.

“One interpretation of these findings is that long COVID could be an atypical form of Alzheimer's and/or that patients who had severe COVID could be predisposed to developing Alzheimer's later in life,” Dr. Marks said, “but much more research needs to be done before we can make more definitive conclusions.”

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