Day: December 19, 2021

Categories : COVIDTags :

Why COVID Cases Vary in Severity

On By ModernMedia
Source: Fusion Medical Animation on Unsplash

Researchers working with ‘humanised mice’ have found why some mild cases of COVID tip over into more severe and life-threatening disease.

An estimated 80 to 90% of people infected with COVID experience only mild cases while 10 to 20% face more severe or life-threatening symptoms.

Yale University researchers working with mice they have engineered to possess human-like immune systems may have found why this is so. Their findings,  published in Nature Biotechnology revealed that the causes of severe COVID may lie in our own antiviral inflammatory response to the virus.

The study also showed that two well-known therapies, monoclonal antibodies and the steroid dexamethasone, can help treat COVID infections. But in the case of the antibodies, treatment is only effective if administered early in the course of disease. In the case of steroids, it’s only effective if administered during later stages of the disease.

Standard laboratory animals and humans have different immune responses, which has made it difficult for scientists to pinpoint the tipping point between mild and severe cases of COVID, so mice engineered to have a human-like immune system, were able to offer an answer.

“If you infect a standard laboratory mouse with SARS-CoV-2 they will get infected, but not get seriously ill,” said Flavell, Sterling Professor of Immunobiology at Yale and senior author of the paper. “But our humanised mice get sick and just don’t get better. Their whole immune system is on fire.”

The research team introduced SARS-CoV-2 virus taken from seriously ill human patients into the nasal passages of their humanised mice and then followed the course of the disease.

They found that the infected mice exhibited the same symptoms as severely ill human patients, such as lung damage, weight loss, and a heightened, persistent inflammatory immune response that damages tissues. They then treated the mice with monoclonal antibodies which specifically target the virus, and were  found to be effective if given before or very early after infection but did little to stifle symptoms if administered in later stages of infections.

Conversely, during the early stages of infection the immune suppressant dexamethasone was fatal to mice when it suppressed the initial immune response that was crucial to combat the virus. However, during later stages of disease, it helped clear infection  by suppressing the inflammatory response that had begun damaging organs.

“Early in the course of disease, a strong immune response is crucial for survival,” said first author Esen Sefik. “Later in the disease, it can be fatal.”

The humanised mice models might also reveal strong clues to the causes and potential treatments of so-called long and severe COVID, the scientists said.

Source: Yale University

Categories : Paediatrics Respiratory DiseasesTags :

Trial Shows Dupilumab is Safe and Effective for Asthma in Children

On By ModernMedia
Source: PIxabay/CC0

In a late-stage clinical trial, the biologic agent dupilumab reduced the rate of severe asthma attacks and improved lung function and asthma control for children ages 6 to 11, adding to the treatment options for children with moderate-to-severe asthma. 

The findings of the international multicentre Liberty Asthma VOYAGE trial, appeared in the New England Journal of Medicine, and informed the agent’s approval in this age group by the Food and Drug Administration.

“This is a really important advance for children with moderate-to-severe asthma and their families,” said Leonard Bacharier, MD, an asthma specialist at Monroe Carell Jr. Children’s Hospital at Vanderbilt and the international lead investigator for the trial.

Asthma is the most common chronic disorder of childhood, according to the Centers for Disease Control and Prevention. It is a leading cause of hospitalisation for children, and children with moderate-to-severe asthma may have reduced lung function and be at greater risk for lung diseases in adulthood, said Dr Bacharier.

“As asthma gets increasingly severe, the burden becomes substantial, impacting the child and the entire family,” he said. “While we have very good asthma therapies available, none of them are perfect in eliminating severe exacerbations.”

Dupilumab, a monoclonal antibody that targets type 2 inflammation, has been approved for the treatment of asthma in adults and adolescents for several years. Based on its established safety and efficacy, the investigators conducted a Phase III clinical trial in 408 children aged 6 to 11 who had uncontrolled moderate-to-severe asthma.

In a double-blind trial, children received either a subcutaneous injection of dupilumab or placebo in addition to their standard therapy every two weeks for a year.

Most participants had markers of type 2 inflammation, namely elevated levels of immune cells called eosinophils and/or elevated levels of nitric oxide in exhaled air. In patients with these markers, dupilumab significantly reduced the rate of severe exacerbations – symptoms requiring systemic steroid treatment, need for emergency care or hospitalisation – by nearly 60%. Additionally, dupilumab improved lung function, measured by forced exhalation, and improved asthma control.

“This is the first study of its kind in children ages 6 to 11 that has demonstrated that a biologic improves asthma exacerbations, lung function and asthma control,” Dr Bacharier said. “We were not surprised, because dupilumab was very effective in clinical trials in adults and adolescents, but we were delighted with the results and the hope they bring to children and their families.”

The trial demonstrated that dupilumab was safe. Some children in the treatment  arm had increases in blood eosinophil levels or mild but manageable parasitic infections (type 2 immunity fights parasites), but very few discontinued dupilumab because of adverse reactions.

Limited ethnic diversity was noted as a weakness in the trial, especially in light of the disproportionate asthma burden among Black people. Trial participants were invited to participate in a trial extension to determine long-term safety and efficacy.

While two other biologic medicines targeting type 2 inflammation have been approved for asthma treatment in children, neither has shown improvements in all three key clinical endpoints – asthma exacerbations, lung function and asthma control – in a controlled clinical trial, Dr Bacharier said.

Bacharier plans to explore the potential for dupilumab to modify asthma development. “Can we use this agent earlier in life to change how the disease develops? I think that’s the next frontier,” he said.

Source: EurekAlert!

Categories : Neurology PaediatricsTags :

Scientists Find Epilepsy Biomarker in Autistic Children

On By ModernMedia
Photo by Ben Wicks on Unsplash

Scientists have discovered that an important brain protein that quiets overactive brain cells and is abnormally low in children with autism, which may explain why so many children with autism also have epilepsy. The findings were published in Neuron.

This protein can be detected in the cerebrospinal fluid, making it a promising marker to diagnose autism and potentially treat the epilepsy that accompanies the disorder.

Mutated versions of this gene were known to cause autism combined with epilepsy, and epilepsy appears in 30% to 50% of children with autism. Autism, which is 90% genetic, affects 1/58 children in the US.

Appropriately nicknamed ‘catnap2’, the protein, CNTNAP2, is produced by the brain cells when they become overactive. Because the brains of children with autism and epilepsy lack sufficient CNTNAP2, scientists found, their brains become overactive, leading to seizures.

For the study, the researchers analysed the cerebrospinal fluid in individuals with autism and epilepsy, and in mouse models. Though, cerebrospinal fluid has been used in researching disorders such as Parkinson’s, this is the first study showing it is an important biomarker in autism.

The new finding about CNTNAP2’s role in calming the brain in autism and epilepsy may lead to new treatments.

“We can replace CNTNAP2,” said lead study author Peter Penzes, the director of the Center for Autism and Neurodevelopment at Northwestern University Feinberg School of Medicine. “We can make it in a test tube and should be able to inject it into children’s spinal fluid, which will go back into their brain.”

Penzes’ lab is currently working on this technique in preclinical research.

The level in the spinal cord is proxy for the level in the brain, explained Penzes. When brain cells are too active because of overstimulation, they produce more CNTNAP2, which floats away and binds to other brain cells to calm them. The protein also leaks into the cerebrospinal fluid, where scientists were able to measure it, giving them a clue for how much is produced in the brain.

Source: EurekAlert!

Categories : CancerTags :

Metformin Ineffective in Most Breast Cancers

On By ModernMedia
Breast cancer cells. Image source: National Cancer Institute on Unsplash

Researchers have found that the diabetes drug metformin, once hoped to hold enormous promise in treating breast cancer, does not prevent or stop the spread of the most common forms of the disease but may still have potential in HER2-positive breast cancer.

The randomised, double-blind trial enrolled 3600 patients who received two pills a day of either placebo or metformin. Overall, researchers found the addition of metformin to standard breast cancer treatments did not improve outcomes in the two most common types of breast cancer, hormone receptor-positive or negative.

“The results tell us that metformin is not effective against the most common types of breast cancer and any off-label use of this drug for the treatment of these common types of breast cancer should be stopped,” said Pamela Goodwin, a professor in the department of medicine at the University of Toronto’s Temerty Faculty of Medicine.

Prof Goodwin presented the findings at the 2021 San Antonio Breast Cancer Symposium.

While metformin was found not to be effective in treating the most common forms of breast cancer, there was evidence that use of metformin for five years might lead to a reduction in deaths from HER2-positive breast cancer, a less aggressive subtype which makes up about 20% of all breast cancers.

“Metformin is not beneficial for use in most common breast cancers, but in the cases of HER2 positive breast cancer, our findings suggest it may be beneficial,” said Prof Goodwin. “These results need to be replicated in future research before metformin is used as a breast cancer treatment, however, it could provide an additional treatment option for HER2-positive breast cancer,” she added

Previous studies suggested metformin may also reduce the risk of development and increase survival of some cancers, including breast cancer.

Metformin was theorised to slow breast cancer growth by improving patient metabolism, notably insulin levels, leading to reduced cancer cell growth, or that it might impact cancer cells directly.

Next steps would be to prospectively test the impact of metformin in patients with HER2-positive breast cancer in a randomised clinical trial. 

Source: University of Toronto

Categories : COVIDTags :

Gauteng Peak Passes but WHO Warns not to Underestimate Omicron

On By ModernMedia
Image by Quicknews

Wastewater monitoring has shown that COVID  infections are falling in Gauteng, indicating that the Omicron wave may have peaked, while the World Health Organization warns that the variant should not be taken lightly despite its mildness.

The findings align with comments by Health Minister Joe Phaahla on Friday that the Omicron-driven wave may be peaking in the province.

Despite Gauteng’s peaking, cases are on the rise in seven of the nine provinces and last week the country saw a new high in cases. Of the infections confirmed on Thursday, Gauteng accounted for 27%, down from 72% of new infections on December 3.

However, the surge of Omicron will likely not be confined to Gauteng. “Early indications are that we might have reached the peak in Gauteng,” Dr Phaahla said in an online media briefing. “But there is a corresponding, rapid increase of cases in the other big provinces.”

He also noted a 70% increase in hospitalisations, though he stressed that this was off of a low base rate. Meanwhile, the WHO has warned that countries should not take the Omicron variant likely in spite of its apparent low severity.

“Countries can – and must – prevent the spread of Omicron with the proven health and social measures.  Our focus must continue to be to protect the least protected and those at high risk,” said Dr Poonam Khetrapal Singh, Regional Director of the WHO South-East Asia Region.

Omicron should not be dismissed as mild, she cautioned, adding that even if it does cause less severe disease, the sheer number of cases could once again overwhelm health systems. Hence, health care capacity including ICU beds, oxygen availability, adequate health care staff and surge capacity need to be reviewed and strengthened at all levels. 

The overall threat posed by Omicron largely depends on three key questions – its transmissibility; how well the vaccines and prior SARS-CoV-2 infection protect against  it, and how virulent the variant is as compared to other variants.

From what we know so far, Omicron appears to spread faster than the Delta variant which has been attributed to the surge in cases across the world in the last several months, Dr Singh said.

She added that emerging data from South Africa suggests increased risk of re-infection with Omicron, and said that there is still limited data on Omicron’s limited severity. Further information is needed to fully understand the clinical picture of those infected with Omicron, and more information is expected in the coming weeks.

Her statements echo those of WHO chief Tedros Adhanom Ghebreyesus, who earlier last week warned that health systems could still be overwhelmed by cases.