The syndrome, which was characterized by persistent fever and inflammation in various organs such as the heart, intestines, and to a lesser extent the lungs, has been reported and has been associated with severe cases
In addition to common symptoms such as fever, cough, and shortness of breath, some children have presented an atypical form of COVID-19 called Pediatric Multisystem Inflammatory Syndrome (SIM-P). Characterized by persistent fever and inflammation in several organs such as the heart, intestines and, to a lesser extent, the lungs, SIM-P has been linked to serious cases and deaths of children from the disease in several countries, including Brazil, since the pandemic began.
When performing the largest series of autopsies to date on children and adolescents who have died as a result of COVID-19, researchers from the Medical Faculty of the University of São Paulo (FM-USP) and the Adolfo Lutz Institute found that The SARS-CoV-2’s high ability to penetrate and damage the tissues of various organs is one of the factors that induce SIM-P and trigger a wide variety of clinical manifestations, including abdominal pain and heartache in addition to persistent fever, failure and seizures.
The results of the FAPESP-sponsored study were published in an article in the Lancet Group’s journal EClinicalMedicine.
“The direct effect of the virus on the tissues of various organs is one of the reasons why children with this syndrome have an exaggerated and altered inflammatory response to the infection,” says Marisa Dolhnikoff, professor at FM-USP and project coordinator at Agência FAPESP.
The researchers performed an autopsy on five children who died of complications from COVID-19 in São Paulo, one boy and four girls between the ages of 7 months and 15 years.
Two children had serious illnesses before they became infected with SARS-CoV-2 – one had cancer and the other had a congenital genetic syndrome – and the other three were previously healthy and developed SIM-P with different clinical manifestations. One of them had inflammation of the heart (myocarditis), another had inflammation of the intestines (colitis), and the third had acute encephalopathy causing seizures.
Autopsies were performed using a minimally invasive method in which tissue samples were taken from all organs by puncture guided by images generated by a portable ultrasound machine.
The presence of SARS-CoV-2 in tissues has been determined by reverse transcription polymerase chain reaction (RT-PCR, the same test used in diagnosing COVID-19) and by immunohistochemistry, a method in which antibodies detect two proteins can from the virus: N from the nucleocapsid and S2 from the “spikes” of the virus surface.
The histopathological analysis showed that the two children with pre-existing severe illness had “classic” severe COVID-19, which was characterized by acute respiratory disease due to extensive and severe injuries from SARS-CoV-2 in the pulmonary alveoli. The virus has also been identified in other organs.
In the three previously healthy children, extrapulmonary inflammatory lesions such as myocarditis in the heart and colitis – an extension of the intestinal inflammation – predominated.
The new coronavirus has been detected in endothelial and muscle cells of the heart in patients with myocarditis, in the intestinal tissue of the child with acute colitis, and in the brain tissue of the child who developed acute encephalopathy.
“We saw that SARS-CoV-2 spreads through blood vessels and infects different types of cells and tissues in these children. And the clinical manifestations were different depending on the target organ, ”says Dolhnikoff.
“It is important that pediatricians consider these possible clinical manifestations other than COVID-19 in children and adolescents so that the infection is diagnosed and SIM-P is treated more quickly,” the researcher emphasizes.
SIM-P can occur a few days or weeks after being infected with SARS-CoV-2. Until then, it was believed that this exaggerated inflammatory response occurred regardless of whether the virus was still present in the body as a result of an immune response.
However, the knowledge gained through the study shows that the manifestations of SIM-P are also triggered by the direct action of the new coronavirus on the cells of organs infected with organs.
“We are not saying that what has been described so far about Pediatric Multisystem Inflammatory Syndrome is wrong, but we add that the tissue damage caused by the virus itself is related and most likely an important component in triggering this response . excessive inflammatory effects in children, ”emphasizes Dolhnikoff.
It is not yet known why some children have an increased inflammatory response to the SARS-CoV-2 infection that characterizes SIM-P. One hypothesis is that there may be a genetic component that has not yet been elucidated.
Endothelial cells are targets
The researchers observed that one of the main targets of the new coronavirus is the endothelial cells that line the inner walls of the vessels, including the large-caliber arteries to the thinner blood capillaries.
“One of the hypotheses is that when infected, the endothelial cell triggers mediators in the bloodstream that cause a cascade of inflammation that triggers all of the reactions that occur in children with SIM-P, such as persistent fever, colitis, myocarditis and encephalitis.” explains Amaro Nunes Duarte Neto, infectious disease and pathologist at FM-USP and the Adolfo Lutz Institute and one of the first authors of the study.
“The virus itself induces this response in the cells, but it is the immune system that creates the harmful response in the patient. However, it is not an autoimmune reaction like the one that occurs in diseases such as lupus, psoriasis, and inflammatory arthritis, which also damage blood vessels. The virus is directly involved in pediatric multi-system inflammation syndrome, ”emphasizes Duarte-Neto.
Electron microscopic analyzes by the professor at the FM-USP Elia Caldini support these conclusions.
The technique enables direct detection of the virus particle with an increase of more than 50,000 fold without the use of specific reactions. It was thus possible to describe the cytoplasmic changes in cells associated with the presence of the virus
“In the search for a unique method of identification, we also used the immunostaining technique of SARS-CoV-2 in electron microscopy in an unprecedented way. We use colloidal gold particles that are coupled to the same specific antibodies that are used in light microscopy against structural proteins from SARS-CoV-2, ”explains Caldini.
The researchers also discovered the formation of microthrombi in children for the first time, similar to what has already been observed and reported in adults.
“Phenomena in connection with blood coagulation must always be taken into account with COVID-19, since electron microscopy shows that blood capillaries are present in all organs examined, which are blocked by the accumulation of red blood cells, leukocytes, cell debris and fibrin with endothelial rupture”, stresses Caldini.