4 DISCUSSION
In the present study involving 182 pediatric COVID-19 patients, we found
that the most common symptoms were fever and dry cough, consistent with
other reports.25 A slightly male dominance was found
in these patients, which was close to that reported in the
USA26 and China.27 Most children
were infected by family cluster, as observed
previously28, which was different from that of adults
who were infected during social activities. A small proportion of
pediatric patients were normal in CT images. As for those with abnormal
CT images, ground glass opacity and patchy shadowing were the most
common features, and consolidation was rare in pediatric patients when
compared to adult patients.
The proportion of patients with allergies and asthma in the current
study was 23.6% (43/182), which was similar to the general prevalence
reported in China.16 Age distribution, sex ratio,
contact history, clinical symptoms, radiological alterations, severity,
treatment and outcomes were not different between allergic and
non-allergic patients. The proportion of COVID-19 children with allergic
rhinitis was 19.8% (36/182), which was also close to the prevalence of
AR recently reported (17.6%) in children of Wuhan.29In consideration of the increasing prevalence of AR in
China,30 it could be concluded that AR is not a
predisposing factor for infection of SARS-CoV-2. Intranasal
corticosteroids should be continued for COVID-19 children with AR, as
stated in a position paper of the European Academy of Allergy and
Clinical Immunology (EAACI).31 There was no evidence
to show that intranasal corticosteroids had any impact on the outcome
and the virus shedding of children with AR.
There was only one asthma children in the current study, suggesting that
asthma is not a predisposing factor for SARS-CoV-2 infection in
children, the same as in adults.22,32This is probably
because angiotensin-converting enzyme-2 (ACE2), the cellular receptor of
SARS-CoV-2, is less expressed in airway epithelia of individuals with
allergic asthma and rhinitis.33 Another possible
reason for rare asthma patients in COVID-19 is that most of asthmatic
patients infected with SARS-CoV-2 were asymptomatic and thus could not
be included in the study. Noticeably, this study involved 10 children
(median age, 3.5 years old) with a history of recurrent wheezing, a
common symptom in preschool children, which is mainly caused by
bronchiolitis and asthma.34 It is not easy to make a
definite diagnosis of asthma in these children, although treatments such
as bronchodilators or inhaled corticosteroids will relieve the
symptom.35
Lymphocytes play an important role in antiviral immunity and contribute
to the cytokine storm responsible for pulmonary and systematic
inflammation of COVID-19 patients. Lymphopenia was common in adult
COVID-19 patients and the degree of lymphopenia was associated with the
severity and outcome of the patients.22,36 However,
fewer patients with lymphopenia were observed in pediatric patients, as
show in the current and previous studies.10,11 This is
consistent with and also the cause of the high prevalence of
asymptomatic and mild courses in COVID-19 children. Interestingly,
eosinopenia was also observed in a significant fraction (29.5%) of
infected children, though the percentage was less than that of adults,
as reported in a previous study that half of the adult COVID-19 patients
had decreased count of eosinophils.22 Given the
positive correlation between lymphocyte counts and eosinophil counts, as
we demonstrated previously, we speculate that decreased Th2 lymphocytes
and cytokines such as IL-5 may be associated with eosinopenia. The
ratios of patients with eosinopenia were not different between allergic
and non-allergic patients, as well as between younger children and older
children. On the other hand, the ratios of eosinophilia were similar
between allergic and non-allergic COVID-19 children. Thus, eosinopenia
could not be used as a diagnostic indicator of COVID-19 in children, in
contrast to that suggested in adults.22
The median levels of total serum IgE in all patients, including allergic
and non-allergic patients, were within the normal range. The ratios of
patients with increased IgE levels were not different between allergic
and non-allergic as well as younger and older children with COVID-19.
Most of the allergic disease in these children was well-controlled AR in
this study, since only few patients were still using intranasal
corticosteroids during the COVID-19. It must be pointed out that no data
about specific IgE, skin prick test or other provocation tests were
available in these patients, which indicates that a few AR patients
might be “misdiagnosed”. Taken together, our results suggest that
allergy has no obvious impact on the disease course of COVID-19 in
children. Other immunoglobins such as total IgG, IgA, IgM, and
complements C3 and C4 were all in normal ranges, without difference
between allergic and non-allergic patients, although higher ratio of
patients with increased IgA, C3 and C4 were seen in older children, and
both ratios of patients with increased and decreased IgG were observed
in younger children.
As far as we know, there is no study focusing on the pediatric COVID-19
children with different severities. Considering that most children
infected with SARS-CoV-2 were asymptomatic or presented as AURI and mild
pneumonia, this is rational. In our cohort, only four children were
categorized as severe or critical cases, including one death due to
intussusception and secondary multiple-organ failure. The other three
severe children were recovered.
Since the rarity of severe and critical pediatric COVID-19 cases, we
compared the clinical and laboratory features of mild pneumonia cases
with those patients without pneumonia. Clinically, mild pneumonia was
associated with more patients with manifestations, especially fever and
cough; in addition, allergy prevalence was not different between the two
groups. In pediatric COVID-19 patients, most of these parameters were in
the normal ranges, except for PCT and CK-MB, both were slightly elevated
in nearly half of the cases, without clinical significance.
Most laboratory findings were comparable between the children with mild
pneumonia and without pneumonia. Some biochemical and immunological
parameters differed between the two groups, but all were in the normal
ranges. These differences may reflect the inflammatory responses induced
by pneumonia. The incidence of elevated PCT, ALP, IL-10 and decreased
complement C3 in pneumonia was higher in mild pneumonia patients than
those without pneumonia. This is a little different from adult COVID-19
patients, that inflammatory biomarkers CRP and PCT, coagulation
indicator D-dimer, myocadiac injury indicator CK/CK-MB, and liver and
renal function indicators ALT, AST, ALP and BUN in the blood were all
elevated and were more prominent in severe and critical cases, as
studies previously demonstrated.22,37
Peripheral lymphocyte subsets alteration has been reported in studies on
adults COVID-19 patients. CD8+ cytotoxic T cells was an independent
predictor for COVID-19 severity and treatment
efficacy.38 CD4+ and CD8+ T cells counts were also
correlated with the disease severity and outcome.39 So
far, there were few studies focusing on the lymphocyte subsets in
pediatric cases. In the present study, we found that in COVID-19
children, both the numbers and percentages of T cells, CD4+ T cells,
CD8+ T cells, B cells and NK cells were mostly in the normal ranges, as
well as the levels of cytokines involved in inflammation, immune
regulation and antiviral immunity such as IL-2, IL-4, IL-6, IL-10, TNF-α
and interferon-γ in the serum. The slight or unchanged immunological
function may contribute to the clinical features of pediatric COVID-19
patients such as lower incidence, milder symptoms, shorter course of
disease and fewer severe cases.40 The median numbers
of total lymphocytes and lymphocyte subsets were different between
younger and older children, but still in the corresponding normal ranges
of their ages. Older children had more changes in the lymphocyte
subsets, including more cases with increased percentages of T cells and
CD8+ T cells, and decreased numbers of B cells. Younger children were
more frequently associated with increased CD4+ T cells numbers and
percentages. Our results provide deep insight into the immunological
features of COVID-19 children. Consistent with the clinical symptoms and
laboratory findings, the lymphocyte subsets and cytokines were not
different in allergic and non-allergic COVID-19 patients. Thus, allergy
plays a negligible role in the incidence, disease course and outcomes of
COVID-19 in children.
Only a minority of children were with evidences of possible co-infection
with other pathogens, most of which was MP, and few were EBV, CMV,
adenovirus and influenza B virus. COVID-19 children with evidence of MP
co-infection were associated with relatively lower monocyte counts and
more azithromycin use, and also lower ratio of ground glass opacity in
chest CT when compared to those without evidence of MP co-infection
(Table S1 and S2). The severity and percentages of children with allergy
were not different between children with or without evidence of MP
co-infection. Thus, MP co-infection might play a minor role in the
disease course of COVID-19 in children. It is noticeable that there were
no patients with evidence of coinfection with rhinovirus (RV) and
respiratory syncytial virus (RSV), which are more commonly found in
children with AR and wheezing.41 During the quarantine
period, many tests performed in commercial institutions were stopped
including RV and RSV detections, which resulted in no RV and RSV
identified in this study. In addition, the physicians tended not to find
other pathogens if the children had been confirmed with SARS-CoV-2
infection by RT-PCR assays. We could not exclude the co-infection in
COVID-19 children with other respiratory viruses, which may also play a
role in the immunity against SARS-Cov-2.
Treatments of COVID-19 children during hospitalization were diverse and
mostly empirical, without evidence of randomized controlled trials
(RCTs). Almost all (97.8%) children were treated with inhalation of
interferon-α, based on the studies and experiences of its usage in
treating other respiratory infection and viral
pneumonia.42 Therefore, we could not know the exact
clinical effects of interferon-α by comparing the outcomes of patients
treated with or without interferon-α. There is no clinical evidence to
address the effect of IFN-α use in COVID-19 children. Therefore, the
treatment of interferon-α should be evaluated with well-designed RCTs in
the future.
In the present cohort, almost all pediatric patients had good outcomes,
except one death. This is consistent with previous report of the outcome
in pediatric COVID-19 patients.9-11 Both patients with
mild and without pneumonia recovered well and were discharged from the
hospital. Duration of hospitalization in this study was not different
between patients with mild and without pneumonia, but shorter than that
of adult patients.37 This is due to the large
proportion of patients without pneumonia, which could be discharged
after a few days of medical surveillance in the hospital. In addition,
the median time from first positive to first negative RT-PCR results of
SARS-CoV-2 were 7 days in both patients with mild and without pneumonia.
This is also shorter than the time needed for virus clearance in adult
patients.37,43 The cause of this difference is
unclear, but it was reported that older age and presence of chest
tightness were independent factors affecting negative conversion of the
virus RNA.43 It may also be associated with different
immunological response between pediatric and adult patients. The
negative conversion of RT-PCR (two consecutive negative results at least
with a 24-hour interval) was one of the discharge criteria, which caused
its positive correlation with the duration of hospitalization.
Interestingly, in patients with pneumonia, the duration of
hospitalization had mildly negative correlation with the level of IFN-γ,
which indicated the possible antiviral roles of interferon. More
importantly, most of children were treated with IFN-α, and its effect on
the negative conversion of virus RNA in respiratory tract sample could
not be excluded.
There are a few limitations of this study. Firstly, not all children in
the designated hospital could be included in the present study;
secondly, the allergic status of most children was according to medical
history, but not with medical records or allergen testing; and the
allergens responsible for the allergy were reported only in 30% of
allergic patients. Thirdly, the dominance of asymptomatic patients and
mild pneumonia prevented most patients from repetitive laboratory tests,
thus the estimation of dynamic variations in blood cell counts and
biochemical parameters was impossible.
In conclusion, pediatric COVID-19
patients tended to have mild clinical course, and severe cases were
rare. Patients with mild pneumonia had higher proportion of fever and
cough and increased inflammatory biomarkers than those without
pneumonia, and the both were with favorable prognosis. Allergic and
non-allergic COVID-19 children were not different in aspects of
incidence, clinical characteristics, laboratory and immunological
findings. Allergy is not a predisposing factor for SARS-CoV-2 infection
and plays no role in the disease course of COVID-19 at least in
children.