“We concluded that many of the symptoms children experience post-COVID-19 are similar to what is seen in adults, but there are some features more unique to children, such as myocarditis, abnormal liver enzymes, hair loss, skin rashes and diarrhea,” said Rao. “There has been a critical need to understand the impact of COVID-19 in children both in the short as well as long-term. This is one of biggest studies we know of to explore what the post-acute sequelae look like in kids. Studies using electronic health record data are a great way to explore research questions that require further confirmation in longer term prospective studies.”

While the presentation has some overlap compared with adults, distinct features exist in children. The risk for PASC appears to be higher in children younger than five years of age, those with medical complexity and those admitted to the intensive care unit with their initial COVID-19 infection.

The exploratory study, “Syndromic, Systemic and Medication Features of Post-acute Sequelae of SARS-CoV-2 Infection in Children and Adolescents: EHR-based Cohort Study from the RECOVER Program,” used electronic health record data from PEDSnet member institutions of 659,286 children tested for SARS-CoV-2 and compared 59,893 children who tested positive with those who tested negative.

The NIH RECOVER Pediatric EHR Cohort investigators conducted a multistate analysis using EHR data of children and people younger than 21 years of age who underwent testing for SARS-CoV-2 at one of eight pediatric health systems in the country between March 1, 2020, and Oct. 31, 2021. Clinicians identified conditions, symptoms and medications associated with PASC in the one to six months following testing. Out of 660,000 children who underwent testing, 9% were positive and most were tested as outpatients.

Symptoms most strongly associated with infection included changes in loss of smell and taste, hair loss, chest pain, abnormal liver enzymes, skin rashes, fever and chills, fatigue and malaise. Conditions most strongly associated with infection included myocarditis, acute respiratory distress and myositis. There was also a higher association with mental health treatment among children who tested positive for PASC compared with those who tested negative.

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“Our study shows that the glymphatic system loses its functionality when an infection occurs in the brain,” says Federico Iovino, associate professor (docent) and group leader at the Department of Neuroscience, Karolinska Institutet and leading author of the study. “Even though we’ve only studied rats so far, we believe it’s possible that the same mechanisms are at play in humans and that the glymphatic system could be a new avenue to explore in the hopes of finding treatments to prevent neurological disabilities caused by bacterial meningitis.”

The glymphatic system was first described in 2013 as a sort of washing-machine that clears waste from the central nervous system, which comprises the brain and the spinal cord. Several neurological diseases, including Alzheimer’s and Parkinson’s disease, have since been associated with its dysfunction.

In this study, the research group of Dr. Federico Iovino and collaborators at the University of Texas Health Science Center at Houston in the U.S. and the University of Southern Santa Catarina in Brazil examined the glymphatic system in rats infected with the bacteria Streptococcus pneumoniae. S. pneumoniae is the leading pathogen causing bacterial meningitis, a potentially deadly infection that in many cases leads to permanent disabilities.

The researchers found higher amounts of bacterial waste products in the brains of rats with meningitis than in a control group. The concentrations were highest in the brain’s cerebrospinal fluid compartments. In contrast, blood tests revealed low levels of bacterial components, indicating the glymphatic system had failed to drain the brain from bacteria and associated rest products. Over time, increased signs of neuroinflammation and neuronal damage were observed, with a corresponding loss of cognitive abilities.

“About half of pneumococcal meningitis survivors suffer from neurological impairments, such as hearing loss, motor and cognitive delay and psychiatric disorders, because of neurons damaged by the infection,” Federico Iovino says. “Since damaged neurons often cannot be repaired or replaced, it is important to find ways to prevent the injury, and the first step in that direction is to understand the molecular mechanisms.”

To further their understanding, the researchers examined brain tissues and cells in detail. They zeroed in on a key fluid transporter, the aquaporin-4 (AQP4)-water channel located at the end-feet of the strings of astrocytes, which are star-shaped cells that act as housekeepers of the glymphatic system.

This water channel normally regulates fluid exchanges between the cerebrospinal fluid compartments and other areas of the brain. But what the researchers found was that during pneumococcal meningitis, the AQP4-water channel lost its natural place and connection with the blood-brain barrier vessel wall. The astrocytic end-feet had detached from the vessel walls after the astrocytes swelled in response to the neuroinflammation caused by the bacterial infection.

“It’s like a snowball effect,” Federico Iovino says. “The infection causes a buildup of toxic bacterial products which activates an immune response that leads to neuroinflammation. The inflammation triggers cellular processes that lead to a detachment of astrocytic end-feet from the blood-brain barrier walls with consequent misplacement and loss of function of the important AQP4-water channel. Combined these events result in a malfunctioning glymphatic system and consequent neuronal damage.”

The study was funded by the Karolinska Institutet Committee for Research, the Karolinska Institutet Research Foundation Grants, the Swedish Research Council, the Bjarne Ahlström Foundation for research in Clinical Neurology, the Clas Groschinsky Foundation, the HKH Crown Princess Lovisa Association for Child Care, the Magnus Bergvall Foundation, the Tore Nilson Foundation, the McGovern Medical School, The University of Texas Health Science Center at Houston, the University of Southern Santa Catarina in Brazil, the Alzheimer’s Association and the National Institutes of Health/National Institute on Aging.

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Despite the impressive power of the immune system’s complex defense network, one type of threat is especially challenging to combat. This arises when the body’s own native cells turn rogue, leading to the phenomenon of cancer. Although the immune system often engages to try to rid the body of malignant cells, its efforts are frequently thwarted as the disease progresses unchecked.The illustration shows a cancer cell (center) surrounded by immune T-cells augmented with an oncolytic (cancer-fighting) virus. A new study describes how a combination of immunotherapy and virotherapy, using myxoma virus, provides new hope for patients with treatment resistant cancers.

In new research appearing in the journal Cancer Cell, corresponding authors Grant McFadden, Masmudur Rahman and their colleagues propose a new line of attack that shows promise for treatment-resistant cancers.

The approach involves a combination of two methods that have each shown considerable success against some cancers. The study describes how oncolytic virotherapy, a technique using cancer-fighting viruses, can act in concert with existing immunotherapy techniques, boosting the immune capacity to effectively target and destroy cancer cells.

Oncolytic viruses represent an exciting new avenue of cancer therapy. Such viruses have the remarkable ability to hunt and terminate cancer cells while leaving healthy cells unharmed, as well as enhancing the immune system’s ability to recognize and terminate cancer cells.

One such virus, known as myxoma, is the focus of the current research and an area of expertise for the research group. The study shows that the use of T-cells infected with myxoma virus can induce a form of cancer cell death not previously observed.

Known as autosis, this form of cell destruction may be particularly useful against solid tumors that have proven treatment-resistant to various forms of cancer therapy, including immunotherapy alone.

“This work affirms the enormous potential of combining virotherapy with cell therapy to treat currently intractable cancers,” McFadden says.

McFadden directs the Biodesign Center for Immunotherapy, Vaccines and Virotherapy at Arizona State University.

Internal sentries

The immune system is composed of a range of specialized cells designed to patrol the body and respond to threats. The system is involved in a ceaseless arms race against pathogens, which evolve sophisticated techniques to attempt to outwit immune defenses, propagate in the body and cause disease. Cancer presents a unique challenge to the immune system as tumor cells often lack the identifying cell features that allow the immune system to attack them by distinguishing self from non-self.

Cancer cells can further short-circuit immune efforts to hunt and destroy them, through a range of evasive strategies. Researchers hope to help the immune system to overcome cancer’s notorious tactics of disguise, developing new experimental techniques belonging to a category known as adoptive cell therapy, or ACT.

Such methods often involve removing a collection of cancer-fighting white blood cells known as T-cells, modifying their seek-and-destroy capacities and reinjecting them in patients. Two forms of ACT immunotherapy are described in the new study: CAR T-cell therapy (CART) and T Cell Receptor Engineering (TCR). The basic idea in each case is the same: treating cancer with activated T lymphocytes extracted from the patient.

New method delivers one-two punch to tumor cells

The development of these therapies has been nothing short of revolutionary, and some cancer patients facing grim prospects have made remarkable recoveries following the use of immunotherapy. But techniques like CART and TCR nevertheless have their limitations and are often ineffective against advanced solid tumors. In such cases, cancer cells often manage to evade destruction by T-cells by downregulating or losing the surface antigens or MHC proteins that T-cells use to identify them.

The new study highlights the ability of immunotherapy when it is coupled with virotherapy to break through the wall of cancer resistance, specifically using myxoma-equipped T-cells. The myxoma can target and kill cancer cells directly but more usefully can induce an unusual form of T-cell directed cell death known as autosis. This form of cell death augments two other forms of programmed cancer cell death induced by T-cells, known as apoptosis and pyroptosis.

During myxoma-mediated autosis, cancerous cells in the vicinity of those targeted by the therapy are also destroyed in a process known as bystander killing. This effect can considerably enhance the dual therapy’s aggressive eradication of cancer cells, even in notoriously hard-to-treat solid tumors.

A combined myxoma-immunotherapy approach therefore holds the potential to turn so-called “cold tumors,” which fly under the immune system’s radar, into “hot tumors” that immune cells can identify and destroy, allowing CAR T-cells or TCR cells to enter the tumor environment, proliferate and activate.

“We are at the edge of discovering newer aspects of the myxoma virus and oncolytic virotherapy,” Rahman says. “In addition, these findings open the door for testing cancer-killing viruses with other cell-based cancer immunotherapies that can be used in cancer patients.”

The ability to radically reengineer oncolytic viruses like myxoma to target a range of resistant cancers provides a new frontier for the treatment of this devastating disease.