Similar with previous study [7], only 37.14% of the children patients showed fever, while cough was most frequent symptoms with a rate of 48.57% (Table 1). A previous study showed that some children COVID-19 cases might display no symptoms or radiologic features of pneumonia, and some might have radiologic features of pneumonia but did not have any symptoms of infection [7]. Notably, 40% of the children cases in our study showed asymptomatic infection before admission (Table 1), however, CT scan of these children showed radiologic features of pneumonia (Table 2). In contrast, 3 of the symptomatic patients showed no radiologic features of pneumonia. All the asymptomatic children cases did the virological tests for investigation, as almost all the patients’ family possessed at least one family member of laboratory confirmed COVID-19 patient. Family cluster of COVID-19 patients were frequently found [10, 20, 21], suggesting that it was easy to transmit among family members, and transmission from family members might serve as the main cause of infection for children. Asymptomatic adult patients were also found with lower rate [4–6], and these patients were also shown to be possible source of infection [22–25]. These asymptomatic patients posed a great threat to the control and prevention of COVID-19, as they were hard to be found unless family members developed symptoms and laboratory confirmed, which is of great concern during the control of COVID-19 pandemic. Meanwhile, there were no statistical differences in epidemiological information, CT scan, blood biochemical and complete blood count between symptomatic and asymptomatic patients (Tables 1 and 2), except a higher level of CRP was found in symptomatic patients, which might contribute to the fever of the symptomatic infection.
Table 1
Epidemiological and clinical features of children cases hospitalized with SARS-CoV-2 infections.
Characteristics
|
SARS-CoV-2 childhood cases
|
P value
|
Total (N = 35)
|
Symptomatic (N = 21)
|
Asymptomatic (N = 14)
|
Median age (range)
|
7 (1.5, 17)
|
8 (1.5, 17)
|
7 (1.5, 13)
|
0.390
|
Age subgroups
|
|
|
|
|
0–1 year
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
1–3 years
|
5/35 (14.29%)
|
3/21 (14.29%)
|
2/14 (14.29%)
|
1.000
|
3–6 years
|
8/35 (22.86%)
|
4/21 (19.05%)
|
4/14 (28.57%)
|
0.511
|
6 ~ 14 years
|
19/35 (54.23%)
|
11/21 (52.38%)
|
8/14 (51.74%)
|
0.782
|
14 ~ 18 years
|
3/35 (8.57%)
|
3/21 (14.29%)
|
0/14 (0%)
|
0.139
|
Male (%)
|
13/35 (37.14%)
|
9/21 (42.86%)
|
4/14 (28.57%)
|
0.392
|
BMI
|
17.1 (15.0, 19.9)
|
17.7 (15.3, 21.1)
|
16.3 (13.88, 18.08)
|
0.083
|
Co-existing chronic medical conditions
|
|
|
|
|
Chronic heart disease
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Chronic lung disease
|
1/35 (2.86%)
|
0/21 (0%)
|
1/14 (7.14%)
|
0.214
|
Chronic renal disease
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Chronic liver disease
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Diabetes
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Cancer
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Initial symptoms
|
|
|
|
|
Fever
|
13/35 (37.14%)
|
13/21 (61.90%)
|
0/14 (0%)
|
< 0.0001
|
Cough
|
16/35 (45.71%)
|
16/21 (76.19%)
|
0/14 (0%)
|
< 0.0001
|
Expectoration
|
1/35 (2.86%)
|
1/21 (4.76%)
|
0/14 (0%)
|
0.407
|
Headache
|
1/35 (2.86%)
|
1/21 (4.76%)
|
0/14 (0%)
|
0.407
|
Myalgia
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Chill
|
2/35 (5.71%)
|
2/21 (9.52%)
|
0/14 (0%)
|
0.234
|
Nausea or vomiting
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Diarrhea
|
1/35 (2.86%)
|
1/21 (4.76%)
|
0/14 (0%)
|
0.407
|
Disease severity
|
|
|
|
|
Severe
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Moderate
|
32/35(91.43%)
|
18/21 (85.71%)
|
14/14 (100%)
|
0.139
|
Mild
|
3/35(8.57%)
|
3/21 (14.29%)
|
0/14 (0%)
|
0.139
|
Exposure history
|
|
|
|
|
Traveling history to Wuhan/Hubei
|
26/35 (74.29%)
|
17/21 (80.95%)
|
9/14 (64.29%)
|
0.269
|
Family cluster
|
32/35 (91.43%)
|
19/21 (90.48%)
|
13/14 (92.86%)
|
0.805
|
Anal swab positive of viral RNA
|
17/35 (48.57%)
|
5/12 (41.67%)
|
8/19 (42.11%)
|
1.000
|
Interval, median days (IQR)+
|
|
|
|
|
Onset to admission
|
0 (0, 3)
|
0 (0, 3)
|
NA
|
NA
|
Admission to discharge
|
17 (13, 22)
|
17 (13, 22.5)
|
16.5 (14, 23.25)
|
0.636
|
Viral co-infections
|
5/35 (14.29%)
|
4/21 (19.05%)
|
1/14 (7.14%)
|
0.619
|
Bacterial co-infections
|
5/35 (14.29%)
|
3/21 (14.29%)
|
2/14 (14.29%)
|
0.531
|
Complications
|
|
|
|
|
Pneumonia
|
32/35 (91.43%)
|
18/21(85.71%)
|
14/14 (100%)
|
0.139
|
ARDS
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Respiratory failure
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Hepatic insufficiency
|
5/35 (14.29%)
|
2/21 (9.52%)
|
3/14 (21.43%)
|
0.324
|
Renal insufficiency
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Cardiac failure
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
Shock
|
0/35 (0%)
|
0/21 (0%)
|
0/14 (0%)
|
1.000
|
NA: Not applicable. |
Studies based on the adult COVID-19 patients have showed that viral shedding of SARS-CoV-2 in the respiratory and fecal samples appeared as early as the first two days from illness onset (d.a.o), peaked during 3–5 d.a.o, decreased during diseases progression, and persisted up to 37 d.a.o [12, 13]. Similar with adult patients, viral RNAs could be detected in both the respiratory and fecal samples from children patients, and lasted up to 33 and 41 d.a.o, respectively (Fig. 2). Unlike adult patients, viral loads in respiratory samples from children seemed to peaked in the very early stage of disease, usually the first d.a.o, and maintained a middle level during 2–7 d.a.o, then gradually decreased to negative. This observation indicated that viral shedding in children patients might also peak on or before illness onset [13]. Of note, a total of 17 patients (48.57%) were tested positive in the fecal samples, despite that only one patient experienced gastrointestinal symptom. Meanwhile, SARS-CoV-2 shedding in stool is much longer and stable than that in respiratory specimens in children COVID-19 patients (Fig. 2). These results highlighted the importance of detecting viral RNAs in fecal samples of children COVID-19 patients. Recently, live virus was successfully isolated from stool [26], and also we isolated the live virus from the rectal swab of a children patient (data not shown), indicating live virus existed in fecal samples. The longer duration of viral shedding in the fecal samples than the respiratory tract (41 vs 33) and the expression of angiotensin-converting enzyme-2 (ACE2) in intestine enterocytes [27, 28], also highlighted the possibility of SARS-CoV-2 infection and replication in the gastrointestinal tract.
Disease severity varied a lot following SARS-CoV-2 infection in adults, from severe ARDS to asymptomatic infections [4–6]. Studies have found that most of the children patients infected with influenza viruses including H5N1, H7N9, and H5N6 avian influenza viruses (AIVs), as well as coronaviruses like SARS-CoV and MERS-CoV showed asymptomatic and mild symptoms [29–34]. In our study, all the included children cases were moderate and mild cases according to the China National Health Commission Guidelines for Diagnosis and Treatment of SARS-CoV-2 infection. Studies have suggested that lymphopenia may associate with disease severity of COVID-19, as 80% of critically ill adult COVID-19 patients experienced lymphopenia, far higher than the adult patients with mild COVID-19 (25%) [5, 6, 35, 36]. Notably, in our study and some other previous report, only a very small portion of children patients experienced lymphopenia [7], which might result from the relatively immature immune system and different immune response compared with adults [37, 38]. This was different from children patients of SARS-CoV infection, which was reported to induce a high portion of lymphopenia up to 46% [34, 37], indicating a different immune response for the two viruses [37]. Another notification is that CD4 and CD8 were normal in children COVID-19 patients (Table 2). However, our previous study has shown that CD4 and CD8 counts were significantly lower in severe and critically ill COVID-19 patients [18], which indicated that the normal CD4 and CD8 counts might also contribute to the mild COVID-19 in children, as CD4 and CD8 cells has been proved to play vital roles in immune responses, including immune regulation, cytokines secretion, virus-specific antibody production and cytolytic activities against target cells [39].
Previous studies have shown that cytokine storm was highly correlated with disease severity and progression [17, 18], and secretion of pro-inflammatory and anti-inflammatory cytokines were found different among different ages of people [38]. So the expression profile of cytokines in children COVID-19 patients upon admission was also analyzed in this study. Similar with adult patients [16–18], elevated concentrations of both pro- and anti-inflammatory cytokines were observed, despite that adult healthy control was used, indicating that cytokine storm also occurred in children following SARS-CoV-2 infection. However, the number of elevated cytokines was far smaller than the adult patients [17, 18]. Furthermore, cytokines which were shown to be highly correlated with disease severity and progression were significantly lower than adult patients, including IP-10, MCP-3, HGF, MIP-1α, and IL-1ra [17, 18]. These results indicated that much weaker cytokine storm happened in children patients, which might also associate with the milder disease in children.