COVID-19 News: Study Warns That SARS-CoV-2 Could Damage Children’s Blood Vessels Leading To Problems In Adult Life And Risk To Long Term Health

COVID-19 News: A new study by researchers from the Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine-Philadelphia warns that the SARS-CoV-2 can in most times damage children's blood vessels, with consequences that might surface decades after the infection subsides.


 
Although most children with SARS-CoV-2 infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C), there is still an underlying threat to their health that has not been properly studied till now.
 
Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population.
 
The study team hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients.
 
The researchers enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001).
 
Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA.
 
Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.
 
The study findings were published in the peer reviewed journal: Blood Advances. https://ashpublications.org/bloodadvances/article/4/23/6051/474421/Evidence-of-thrombotic-microangiopathy-in-children
 
Lead researcher, Dr David Teachey, MD, an oncologist and hematologist at Children's Hospital of Philadelphia in Pennsylvania said that alarmingly a high proportion of the children in the study met the clinical criteria for thrombotic microangiopathy (TMA).
 
He warned that even children with a mild or asymptomatic case of COVID-19 might have TMA, with potential risk to their long-term health and also in their adult life.
 
One proposed mechanism for SARS-CoV-2–mediated TMA is via complement activation.  https://pubmed.ncbi.nlm.nih.gov/32271624/
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https://pubmed.ncbi.nlm.nih.gov/32733003/
 
https://pubmed.ncbi.nlm.nih.gov/32759504/
 
https://pubmed.ncbi.nlm.nih.gov/32877502/
 
Complement dysregulation results in unregulated formation of the C5b9 membrane attack complex, leading to the clinical manifestations of TMA.
 
Soluble C5b9 (sC5b9) is a clinically available biomarker and has been implicated as an indicator of severity in hematopoietic stem cell transplant–associated TMA (HSCT-TMA), as patients with markedly elevated sC5b9 have increased mortality. https://pubmed.ncbi.nlm.nih.gov/24876561/
 
In mouse models of the related coronaviruses (SARS-CoV and Middle East respiratory syndrome coronavirus), knockout or blockade of components of the alternative complement pathway led to amelioration of severe respiratory syndromes and a decrease in cytokine production. https://pubmed.ncbi.nlm.nih.gov/29691378/
 
He told Thailand Medical News, "We cannot just assume that all children with SARS-CoV-2 infection do just fine."
 
Dr Teachey however he stressed that the finding is preliminary, its implications are uncertain, and treatments that are already available might reduce the risk.
 
It was found that typically in adults with COVID-19, endothelial cell damage to small blood vessels can result in TMA, leading to hemolytic anemia, thrombocytopenia, and sometimes organ damage. https://pubmed.ncbi.nlm.nih.gov/32343504/
 
https://pubmed.ncbi.nlm.nih.gov/32381264/
 
https://pubmed.ncbi.nlm.nih.gov/32437596/
 
https://pubmed.ncbi.nlm.nih.gov/32271624/
 
https://pubmed.ncbi.nlm.nih.gov/32733003/
 
Importantly, in children with cancer, TMA has been associated with an increased risk of severe illness late in life, such as high blood pressure, early kidney damage, or cardiovascular disease. https://pubmed.ncbi.nlm.nih.gov/25483393/
 
Dr Teachey  stressed, "It can be a harbinger of things more serious when you get to be a lot older, which is one of the reasons that we need to study it."
 
Typically, thrombotic microangiopathy  or TMA may come about when complement dysregulation causes unregulated formation of the C5b9 membrane attack complex. And soluble C5b9 (sC5b9) may also serve as a biomarker of the condition.
 
It has been found that most children with COVID-19 have no symptoms or only mild ones. Some, most often teenagers with other underlying health problems, develop severe respiratory symptoms requiring hospitalization. https://pubmed.ncbi.nlm.nih.gov/32320004/
 
https://pubmed.ncbi.nlm.nih.gov/32766542/
 
However a few develop multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome characterized by fever, inflammation, and organ dysfunction in the setting of recent SARS-CoV-2 infection. As its name implies, the condition is extremely rare in adults. https://pubmed.ncbi.nlm.nih.gov/32598831/
 
https://pubmed.ncbi.nlm.nih.gov/32386565/
 
https://pubmed.ncbi.nlm.nih.gov/32598830/
 
It is now known that severe MIS-C involves shock and cardiovascular collapse, with as many as 80% of those afflicted needing care in a pediatric intensive care unit.
 
Importantly it appears to be a post-infectious immune-mediated condition distinct from other manifestations of SARS-CoV-2. It can occur weeks or months after a SARS-CoV-2 infection, and is thus seen as separate from COVID-19.
 
In order to see whether the virus causes TMA in children, Dr Teachey and colleagues studied 50 hospitalized pediatric patients with acute SARS-CoV-2 infection and compared laboratory findings with those of 26 children without the infection.
 
The study team found that sC5b9 levels were higher in those infected than those who weren't. Those with infection also had higher sC5b9 levels than normal (257 ng/mL or less). 
 
In the study, minimal COVID-19 was defined as "an incidental finding of COVID-19 during routine testing before admission or a procedure, or those with mild COVID-19 symptoms that did not require noninvasive mechanical ventilation."
 
Significantly sC5b9 levels were significantly different between children with and without infection (P < .001), but not among those with different severities of infection.
 
It was also found that elevations in sC5b9 were significantly correlated with maximum creatinine and blood urea nitrogen levels, and were higher in patients with acute kidney injury. And there was evidence of acute kidney injury in 10% of patients with minimal COVID-19, 36% with severe COVID-19, and 28% with MIS-C.
 
The study team was able to obtain peripheral blood smears for 34 patients. They found schistocytes, another indication of TMA, in 45% of patients with minimal COVID-19, 87% with severe COVID-19, and 87% with MIS-C.
 
The study team found that of 19 patients with an available blood smear, complete blood count, and lactate dehydrogenase level, 17 (89%) met clinical criteria for TMA. sC5b9 levels were elevated both in patients who did and did not meet criteria for TMA.
 
The study team said that more studies are needed before clinicians can make use of biomarkers for TMA in children with SARS-CoV-2 infections.
 
Dr Teachey added, "We could find out that this doesn't really have any clinical implications, that they get a virus that causes some irritation to their blood vessels, but they're children, they can heal and get better from lots of different things.”
 
He further added, "Or we could find that in a percentage of children with SARS-CoV-2 infection who seem relatively healthy, it could be causing some damage to blood vessels that could lead to long-term complications."
 
Chief of cardiology at Lurie Children's Hospital and Northwestern University in Chicago, Illinois, Dr Stuart Berger, MD, agreed that the study finding points to an important area of research.
 
He said, "It may not help us today or tomorrow, but it raises some interesting concepts about the pathophysiology. For instance, if sC5b9 proves to be a reliable predictive biomarker for MIS-C, it could help determine which children who test positive for SARS-CoV-2 should be closely followed.”
 
Should additional and further research confirm the importance of complement proteins in TMA, then existing drugs that target these proteins might prove useful.
 
A potential pharmaceutical candidate such drug, eculizumab, is a key treatment for hematopoietic stem cell transplant–associated TMA. However, these treatments would likely be reserved for the most severely ill because of associated side effects. Blood thinners could also have a role. https://pubmed.ncbi.nlm.nih.gov/32369610/
 
https://pubmed.ncbi.nlm.nih.gov/32327719/
 
https://pubmed.ncbi.nlm.nih.gov/32961333/
 
The study team concluded, “We have shown that terminal complement activation is present in children across the spectrum of SARS-CoV-2 infection and that a high proportion of these children met clinical criteria for TMA. Elevations in sC5b9 occur independently of other laboratory markers associated with COVID-19 and MIS-C, and are associated with evidence of renal dysfunction. Although additional studies are clearly needed, evaluation for clinical TMA and complications of TMA should be considered in hospitalized children with SARS-CoV-2. The long-term implications of complement activation and TMA in these children need to be studied.”
 
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