Discussion
In our study, performed in regions of Germany with a relatively high
incidence of COVID-19 in adults in the first phase of the pandemic,
approximately 6% of children tested positive for SARS-CoV-2 antibodies
in two tests directed against the N and S proteins of the virus. Of
those children with high N-protein specific antibody levels, 18 showed
signs and symptoms suggestive for mild to moderate forms of PMIS weeks
to months after the suspected infection with SARS-CoV-2.
Within this subgroup, sera of
children with symptoms showed significantly lower neutralizing capacity
as compared to sera from children without PMIS or PMIS-like symptoms.
This study was not primarily aimed to investigate representative
prevalence rates of SARS-CoV-2 infections in children in Germany in the
first wave,15 but to answer the question if screening
of children for SARS-CoV-2 antibodies may help to detect those at
increased risk for PMIS. Despite the closing of schools, kindergartens
and nurseries very early on in the pandemic in Bavaria, a surprisingly
high number of children showed antibodies in our study. One possible
explanation for that could be that many parents who participated in the
study suspected a coronavirus infection in their children due to
symptoms or outbreaks in the community. Indeed, children were explicitly
not tested in the beginning of the pandemic when test capacities were
limited. Thus, the study may have addressed an unmet need of parents to
get their children tested, which was further supported by the
observation that participation in the study was overwhelming.
We used values beyond S/Co of 100 in the Elecsys test as a proxy for
strong antibody responses, as this value is approximately the
97th percentile of all previous available test values
(provided by Roche, personal communication). We are aware that the assay
is a qualitative test but nevertheless, in the absence of a better
measure to determine strong antibody responses at the early point in the
pandemic, we applied it in the context of a study in this first
screening approach. Surprisingly, almost 70% of seropositive children
with a mild to asymptomatic course of the initial SARS-CoV-2 infection,
had such values compared to only 21% of seropositive adults with mild
disease in one of our previous studies.16 These data
may suggest that children mount stronger antibody responses to
SARS-CoV-2 than adults on a regular basis. It can also be speculated
that this may contribute to milder acute course of the initial infection
as observed in children. In contrast, high levels of S-specific
antibodies seem to worsen the outcome in severe courses of COVID-19 in
adults.17 This hypothesis should be further l
investigated in longitudinal studies.
Many children show values of S/Co beyond 100 in the Elecsys test, and a
similar observation was made for the S protein based in-house test,
where also high values were observed in more than half of the positively
tested individuals. As we included only children with strong N-specific
antibody responses in our follow-up, we may have missed some children
that developed PMIS. Due to the anonymous design of our study, we cannot
go back to study participants and extend the follow-up to those with
lower antibody values. However, this would be needed to investigate
possible cutoff points in antibody responses, which could predict PMIS
with greater specificity and/or sensitivity. Therefore, it seems a good
strategy at this point to evaluate all children who show antibody
responses to SARS-CoV-2 for PMIS symptoms.
Our study indicates that very few symptoms are specific for COVID-19 in
children. On the other hand, only 23% of the 162 children with
detectable SARS-CoV-2 antibodies were free of symptoms in the weeks
before the antibody test. Interestingly, even children as young as 6
years of age were able to indicate loss of smell and taste - the only
specific symptom for COVID-19 we could identify in children. Thus,
screening for SARS-CoV-2 infections in children by symptoms does not
seem to be useful.
A large number of children acquired antibodies against SARS-CoV-2 when
family members had developed COVID-19. Therefore, we suggest that
children confronted with COVID-19 in the household should systematically
be screened for SARS-CoV-2 antibody responses, e.g. 4 weeks after the
diagnosis in the index case, thereby not missing out on potential
childhood SARS-CoV-2 infections despite of mild or absent symptoms in
children.
In our study population, at least 2 children showed PMIS with cardiac
affection (A-V block grade I; thoracic pain and left axis deviation),
even though the children were not recognized to be sick enough to be
referred to the hospital. Of note, our study also identified 2 siblings
of study participants (tested positive for SARS-CoV-2 antibodies outside
the study) with cardiac PMIS symptoms. Furthermore, it became clear in
the course of the study that initially mildly affected children suffer
from long-term COVID-19 effects. As reported in adults
,18 we identified a case of chronic fatigue syndrome
timely associated with SARS-CoV-2 infection. Thus it seems necessary to
follow up children after a COVID-19 infection for neuropsychological
effects of COVID-19.
We found a significant correlation between PMIS / PMIS-like symptoms and
low neutralization titers within a subgroup of children with high titers
of N-specific antibodies. Lower neutralization titers were also found in
severe PMIS compared to active COVID-19.19 Our
observation that lower neutralization capacities are associated even
with mild PMIS symptoms suggests that this may at least contribute if
not cause the development of PMIS. Further studies need to confirm the
predictive value of high N-specific antibodies and clarify whether or
not high N-specific antibody titers and low neutralization capacity are
independent predictors for the development of PMIS and PMIS-like
symptoms.
Based on our results we propose to screen children from households with
COVID-19 cases on a regular basis for SARS-CoV-2 antibodies as well as
children from areas with high prevalence of COVID-19, if any symptoms
suggestive for COVID-19 occur. Those that are found to have antibodies,
no matter if S protein or N protein directed, should be offered a
clinical follow-up for PMIS. Based on the experience with Kawasaki
disease,20 early intervention seems to have the
potential to avoid long-term or chronic illness also in PMIS.