Improving detection of SARS-CoV-2 infection among severely ill children

Researchers in the UK have conducted a study showing that children with a severe inflammatory syndrome had high levels of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), despite having tested negative for the virus by polymerase chain reaction (PCR).

The fact that these patients presented with a syndrome where the cause was only determined through antibody screening is important, says the team because serology has not previously been useful for diagnosing SARS-CoV-2 infection.

Eight children presenting with a multi-system inflammatory syndrome and features of Kawasaki disease and toxic shock syndrome - Pediatric Inflammatory Multisystem Syndrome- temporally associated with SARS-CoV-2 pandemic (PIMS-TS) - had high levels of IgG and IgA antibodies against SARS-CoV-2, while PCR had not indicated any evidence of infection.

Alex Richter (Institute of Immunology and Immunotherapy, University of Birmingham) and colleagues say the study results suggest that serology may be a valuable tool for understanding illnesses caused by SARs-CoV-2.

They also suggest that the “PIMS-TS” definition may need amending to reflect that the syndrome is triggered by SARS-CoV-2, rather than temporarily being associated with the pandemic.

A pre-print version of the article can be accessed on the server medRxiv* while the article undergoes peer review.

SARS-CoV-2 usually poses a greater risk to adults than children

During the coronavirus disease 2019 (COVID-19) outbreak, SARS-CoV-2 has caused dangerous respiratory infections in adults that are associated with a high mortality rate, particularly among the elderly and those with underlying health conditions such as diabetes and cardiovascular disease.

By contrast, infection is generally asymptomatic among children and is associated with a low mortality rate.

However, reports have recently emerged of children presenting with features of PIMS associated with SARS-CoV-2 infection.

Testing for the virus using PCR often generates a negative result for these children, making it difficult to tell whether the syndrome arises as a late complication of SARS-CoV-2 infection or reflects increased surveillance due to the pandemic.

The antibody response following infection

Following infection with SARS-CoV-2, an IgM antibody response develops first and then diminishes later, at which point levels of IgG increase, and this becomes the dominant antibody response.

“Thus, high levels of IgG in the absence of IgM are typically suggestive of infection weeks or even months previously,” writes the team.

Now, Richter and colleagues have used an ELISA test to screen for antibodies against SARs-CoV-2 among eight children, aged a median of nine years, who had been admitted to hospital with features of PIMT-TS between 28th April and 8th May 2020.

All the children had tested negative for current SARS-CoV-2 infection by PCR.

The ELISA test results were compared with pre-pandemic control serum samples and plasma samples from adults with severe COVID-19 infections who had required intensive care.

What did the researchers find?

All the children had high levels of IgG and IgA. Further analysis showed that the IgG antibodies were of the subclasses (IgG1 and IgG3) that have also been observed in samples taken from adults hospitalized with COVID-19.

Unlike the adults, who had high levels of IgM, children did not test positive for these antibodies.

The authors say this would be consistent with SARS-CoV-2 infection having occurred weeks previously and PIMS-TS having manifested long after viral clearance.

“After testing hundreds of pre-pandemic control sera, we have found minimal cross-reactivity of pre-pandemic sera with the spike glycoprotein, indicating our assay is highly specific for SARS-CoV-2 and that this virus is indeed the aetiological trigger,” writes the team.

The authors say the absence of current infection among the children suggests that the disease features they present with are related to immune-mediated pathology.

Activation of the complement system may be involved

This immune-mediated pathology has previously been proposed as contributing to disease severity in cases of COVID-19 among adults.

“Associated with this is the detection of IgG1 and IgG3 in these children. These isotypes are associated with complement activation, which has been shown to be enhanced in adult patients,” the researchers add.

The authors say the findings offer “a widening of the value of serology in the identification and understanding of infections caused by SARS-CoV-2.”

Furthermore, “it may be worth considering amending the definition of PIMS-TS so that TS is not just ‘temporally associated with SARS-CoV-2 pandemic,’ but ‘triggered by SARS-CoV-2 infection,’” concludes the team.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally has a Bachelor's Degree in Biomedical Sciences (B.Sc.). She is a specialist in reviewing and summarising the latest findings across all areas of medicine covered in major, high-impact, world-leading international medical journals, international press conferences and bulletins from governmental agencies and regulatory bodies. At News-Medical, Sally generates daily news features, life science articles and interview coverage.

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