Researchers have discovered the mechanisms in children with COVID-19 who present with multisystem inflammatory syndrome


Researchers have discovered the blood clotting and immune protein pathways that are activated in severe cases of COVID-19 in children, paving the way for earlier diagnosis and more targeted treatments.

The study led by the Murdoch Children’s Research Institute (MCRI) and the University of Melbourne and published in Nature Communications, has identified disease mechanisms in children with COVID-19 who present with multisystem inflammatory syndrome, where different body parts can become inflamed including the heart, lungs, and brain and acute respiratory distress syndrome, a type of lung disease.

MCRI researcher and University of Melbourne Ph.D. student Conor McCafferty said the main triggers for severe COVID-19 in children were blood clotting and how proteins in the immune system reacted to the virus.

“Children are in general less susceptible to COVID-19 and present with milder symptoms, but it remained unclear what caused some to develop very severe disease,” he said.

“Our research was the first to uncover the specific blood clotting and immune protein pathways impacted in children with COVID-19 who developed serious symptoms.”

For the study, blood samples from 20 healthy children were collected at The Royal Children’s Hospital and samples from 33 SARS-CoV-2 infected children with multisystem inflammatory syndrome or acute respiratory distress syndrome were collected from the Hôpital Necker-Enfants Malades, Greater Paris University Hospitals.

Professor Damien Bonnet, from the Hôpital Necker–Enfants Malades, Greater Paris University Hospitals, said collecting samples to further describe the mechanisms of these syndromes and establishing worldwide collaborations were considered key issues to improve treatment and outcomes.

The research found 85 and 52 proteins were specific to multisystem inflammatory syndrome and acute respiratory distress syndrome, respectively. Both syndromes are major potential outcomes of severe COVID-19.

Mr McCafferty said the discoveries were possible due to proteomics, an experimental approach that allowed the researchers to investigate almost 500 proteins circulating in the blood at once.

Data shows 1.7 percent of reported pediatric hospitalized cases of COVID-19 included admission to the Intensive Care Unit. Children with COVID-19 who present with multisystem inflammatory syndrome also show similar clinical features to Kawasaki disease and toxic shock syndrome such as fever, abdominal pain, vomiting, skin rash and conjunctivitis, making it difficult to quickly diagnose patients.

MCRI Professor Vera Ignjatovic said the results provided an understanding of the processes that underly severe COVID-19 in children, which would help in the development of diagnostic tests for early identification of children at risk, as well as therapeutic targets to improve the outcomes for those with severe cases.

“Knowing the mechanisms associated with severe COVID-19 in children and how the blood clotting and immune systems in children react to the virus will help diagnose and detect acute COVID-19 cases and allow us to develop targeted treatment,” she said.

Multisystem inflammatory syndrome in children (MIS-C) emerged during the new coronavirus disease (COVID-19) pandemic, when children hospitalized in the United Kingdom (UK) and other countries from March to May 2020 developed fever and multisystem inflammation and, in severe cases, shock and multiple organ failure.1 The hypothesis of association with SARS-CoV-2 was then considered.2

MIS-C is known as an inflammatory condition that appears after the acute phase of infection, suggesting post-viral immune dysregulation that leads to a hyperinflammatory state.3,4 MIS-C shares characteristics with Kawasaki disease, toxic shock syndrome, bacterial sepsis, and macrophage activation syndrome.

Adults with COVID-19- associated “cytokine storm” syndrome also had clinical and laboratory characteristics similar to familial hemophagocytic lymphohistiocytosis or macrophage activation syndromes, such as: elevations of serum ferritin levels, liver enzymes, soluble interleukin-2 (IL-2) (sCD25) receptor, D-dimer, clotting times (prothrombin time and activated thromboplastin time) and lactic dehydrogenase (LDH), thrombocytopenia and lymphopenia.5

So far there are no universally accepted protocols for MIS-C management, so many organizations have published their own protocols.3–7 In Brazil, the diagnosis of MIS-C is established by the criteria proposed by the Ministry of Health (MH): hospitalized cases with presence of high (>38° C) and persistent (≥3 days) fever in children and adolescents (up to 19 years old) and at least two of the following signs and/or symptoms: non-purulent conjunctivitis or bilateral skin lesion or signs of mucocutaneous inflammation (oral, hands or feet); hypotension or shock; manifestations of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities – including echocardiogram findings, elevated troponin or N-terminal B-type natriuretic peptide (NT-proBNP) – evidence of coagulopathy (due to increased prothrombin time, partially activated thromboplastin time, or D-dimer); acute gastrointestinal manifestations (diarrhea, vomiting or abdominal pain).

Patients must have high inflammation markers [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) or procalcitonin (PCT), among others), any other causes of infectious and inflammatory origin, including bacterial sepsis, staphylococcal or streptococcal shock syndromes must be ruled out. Also, there must be evidence of COVID-19 (molecular biology, positive antigenic or serological test) or history of contact with a COVID-19 case.5,6

The Royal College of Pediatrics and Child Health (RCPCH) case definition is described below. 1) A child presenting with persistent fever, inflammation (neutrophilia, elevated CRP and lymphopenia) and evidence of single or multi-organ dysfunction (shock, cardiac, respiratory, renal, gastrointestinal or neurological dysfunction) with additional features: clinical (all—persistent fever >38.5°C; most—oxygen requirement, hypotension; some—abdominal pain, confusion, conjunctivitis, cough, diarrhea, headache, lymphadenopathy, mucus membrane changes, neck swelling, rash, respiratory symptoms, sore throat, swollen hands and feet, syncope, vomiting); laboratory tests (all—abnormal fibrinogen, absence of potential organisms other than SARS-CoV-2, high CRP, high D-dimers, high ferritin, hypoalbuminemia, lymphopenia, neutrophilia (in most, neutrophils in some); some—acute kidney injury, anemia, coagulopathy, high IL-10 or IL-6 (if available), neutrophilia, proteinuria, raised creatine kinase (CK), raised LDH, raised triglycerides, raised troponin, thrombocytopenia, transaminitis); echocardiogram/electrocardiogram (ECG)—myocarditis, valvulitis, pericardial effusion, coronary artery dilatation; Chest X-ray: patchy symmetrical infiltrates, pleural effusion; abdominal ultrasound: colitis, ileitis, lymphadenopathy, ascites, hepatosplenomegaly; chest computed tomography scan (CT): may demonstrate coronary artery abnormalities.

This may include children meeting full or partial criteria for Kawasaki disease. 2) Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus (waiting for results of these investigations should not delay seeking expert evaluation). 3) Reverse transcriptase followed by polymerase chain reaction (RT-PCR) for SARS-CoV-2 may be positive or negative.7

Patients can rapidly progress to severe forms of the disease with acute respiratory failure, acute kidney disease, hypotension, acute heart failure and shock. Thus, the goal of treatment is to reduce the hyper inflammatory state and restore organs and systems functions, reducing sequelae such as coronary artery lesions and cardiac dysfunction, in addition to reducing mortality.5

As this is a new and potentially serious condition coupled with the need for more knowledge on the subject, we present a series of six cases of MIS-C treated at a tertiary pediatric hospital in southern Brazil.

reference link :

More information: Pathophysiological pathway differences in children who present with COVID-19 ARDS compared to COVID-19 induced MIS-C, Nature Communications (2022). DOI: 10.1038/s41467-022-29951-9



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