Direct action of SARS-CoV-2 on organs may lead to exacerbated inflammatory response in pediatric patients

In addition to common symptoms such as fever, cough, and respiratory distress, some children have an atypical form of COVID-19 known as childhood multisystem inflammatory syndrome (MIS-C), characterized by persistent fever and inflammation of various organs, such as the heart and brain. intestines and to a lesser extent the lungs. Reports of MIS-C have been increasingly associated with serious cases and deaths in several countries, including Brazil, since the start of the pandemic.

Researchers associated with the University of São Paulo Medical School (FM-USP) and the Adolfo Lutz Institute in Brazil have performed the largest series of autopsies to date on children who died from COVID-19. Their findings show that the ability of SARS-CoV-2 to invade and damage various organs is one of the factors leading to MIS-C, causing a wide variety of clinical manifestations, including abdominal pain, heart failure and seizures. as well as persistent fever.

The study was supported by São Paulo Research Foundation – FAPESP and reported in an article in EClinicalMedicine, a journal of the Lancet group.

The direct action of the virus on the tissues of various organs is one of the reasons why children with this syndrome have an aggravated and altered inflammatory response to infection.”

Marisa Dolhnikoff, last author of the article, professor at FM-USP

The researchers performed autopsies on five children who died of COVID-19 in São Paulo: a boy and four girls between the ages of 7 months and 15 years. Two were seriously ill before being infected with SARS-CoV-2, one with cancer and the other with a congenital genetic disorder.

The other three were previously healthy and developed MIS-C with different clinical manifestations. One had myocarditis (inflammation of the heart muscle), another had colitis (inflammation of the gut), and a third had acute encephalopathy (brain damage) with seizures.

A minimally invasive technique, ultrasound guided with coaxial and punch needles, was used to collect tissue samples from all major organs. The presence of SARS-CoV-2 in the samples was determined by real-time reverse transcription polymerase chain reaction (RT-PCR, the technique also used to diagnose COVID-19) and by immunohistochemistry, using antibodies to detect the viral nucleocapsid protein (N) and one of the spike proteins (S2).

Histopathological analysis showed that both children with severe pre-existing disease had “classic” severe COVID-19 characterized by acute respiratory distress due to extensive damage to the alveoli caused by SARS-CoV-2. The virus was also found in other organs.

The three previously healthy children were found to have inflammatory lesions outside the lungs, such as myocarditis and colitis. The virus was detected in endothelial and muscle cells of the heart of the patient with myocarditis, in intestinal tissue of the child with acute colitis, and in brain tissue of the patient with acute encephalopathy.

“We found that SARS-CoV-2 had spread through blood vessels throughout the body, infecting different types of cells and tissues in these children. The clinical manifestations varied depending on the target organ,” Dolhnikoff said. “It is important for pediatricians to pay attention to these potential differences in the clinical manifestations of COVID-19 in children of all ages so that the infection is diagnosed and MIS-C can be treated at an early stage.”

MIS-C can occur several days or weeks after infection with SARS-CoV-2. The runaway inflammatory response was thought to occur whether or not the virus was still in the organism as a result of the immune response, but the study found evidence that the manifestations of MIS-C are also caused by the virus’ direct action on the cells of infected organs.

“We’re not saying that everything described so far about the multisystem inflammatory syndrome in children is wrong. We’re just adding the observation that the damage to tissues by the virus is associated with this exacerbated inflammatory response in children, and very likely a key is component in its inductance,” Dolhnikoff said.

Why some children respond to infection by SARS-CoV-2 with the exacerbated inflammation characteristic of MIS-C is unknown, but the response may contain a genetic component.

Targeted endothelial cells

The researchers found that the main targets of the virus were endothelial cells, which line blood vessels of all shapes and sizes and regulate exchange between the bloodstream and surrounding tissues. “One hypothesis is that when an endothelial cell is infected, it activates mediators in the bloodstream that trigger an inflammatory cascade and the other responses seen in children with MIS-C, such as persistent fever, colitis, myocarditis and encephalitis,” said Amaro Nunes Duarte. Neto, first author of the article. Duarte Neto is an infectious disease specialist and pathologist at FM-USP and Adolfo Lutz Institute.

“The virus induces these responses in the cells, but it is the immune system that produces a response with adverse effects on the patient,” he said. “However, it is not an autoimmune reaction, as we see in lupus, psoriasis or inflammatory arthritis, which also involves damage to blood vessels. In MIS-C, the virus is directly involved.”

Electron microscopy analysis by Elia Caldini, a professor at FM-USP, supported these conclusions. Electron microscopes directly magnify viral particles more than 50,000 times, without the use of reagents. The technique allowed the researchers to describe changes in the cell cytoplasm associated with the presence of the virus.

“To unambiguously confirm our identification of the virus, we were the first to use SARS-CoV-2 immunolabeling in combination with electron microscopy,” Caldini said. “We linked colloidal gold particles to the specific antibodies used in light microscopy against structural viral proteins.”

The researchers also discovered microthrombi (small blood clots) in children for the first time. This had already been observed and reported in adults. “Phenomena related to blood clotting should always be considered in COVID-19.

Our electron microscopy analysis showed that capillary blood vessels in all organs were blocked by accumulated red and white blood cells, cell debris and fibrin, disrupting the endothelial wall,” Caldini said.

Source:

São Paulo Research Foundation (FAPESP)

Reference magazine:

Duarte-Neto, AN, et al. (2021) An autopsy study of the spectrum of severe COVID-19 in children: from SARS to different phenotypes of MIS-C. ECKlinical Medicine. doi.org/10.1016/j.eclinm.2021.100850.

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