Discussion
According to data reported by our hospital,5 RP patients have clinical characteristics of younger age and milder symptoms, and according to the 39 pediatric patients we observed in previous follow-up, most of them are mild symptoms, and there is no severe patient. Our study found that children have a higher incidence of RP compared with adults. However, there was no statistically significant difference between the RP group and the control group in terms of age, gender distribution, clinical symptoms, CT positive findings, and incidence of co-infection. Children with RP have a higher proportion of family cluster infections.9-10 According to our observation, other patients in the family are generally cured first and close contacts were also without RP during followed-up, which can basically rule out the possibility of infecting children from other family members. However, it is still unknown whether children with RP are still infectious, because the children have to be isolated at home for 2 weeks after discharge and almost have no contact with the outside world.This also indicates us that SARS-CoV-2 is extremely resilient.11It seems to coexist peacefully with humans. In any case, disinfection of household environment and hand hygiene must be the top priority for disease prevention and control.12
The underlying risk factors of high incidence of RP and the viral clearance mechanism in children are still not completely understood.13 T lymphocyte and phagocyte function may play an important role.T lymphocytes help clear viruses and regulate innate immune system responses.Chu et al demonstrated that MERS-CoV infection can induce T cells apoptosis through the activation of external and intrinsic apoptotic pathways.14Coleman et al found that the depletion of CD4+ T cells, CD8+T cells or macrophages had no effect on the replication of MERS-CoV in infected lungs of mice.15 Earlier studies have revealed that SARS-CoV,which share the same cell entry receptors with SARS-CoV-2,could infect immune cells,including T lymphocytes, monocytes,and macrophages.The CD4+ and CD8+ T cells counts decreased at the onset of illness.16-17These studies indicated that the reduction of T cells is likely to contribute to the continuous replication and RP of SARS-CoV-2. However, our investigation did not observe this similar change and no significant difference between the two groups. After analysis,there may be the following reasons. First, the sampling time point may be in the early stage of the disease, the children’s immune system is imperfect, and the response is relatively slow and lagging. This may also explain why children are asymptomatic or mild, but the incidence of RP is high.3,5 Second, the sample size is small, and there are many missing values in the control group, which may be different from the true level.These also suggest that CD4+ and CD8+ T cells count may not be suitable to be predictors of RP.
The average WBC level of pediatric patients in our investigation is totally within the normal reference range, which is consistent with related reports,18 but WBC in the RP group is significantly higher than the control group.As far as we know, there is still no accurate answer to why the WBC in the RP group is higher than the control group. However, PCT, hs-CRP, IL-6 are within the normal range and there is no difference between the two groups.Obviously,the impact of co-infection is negligible.We speculate that this may be related to the weak response of the innate immune system and the reduction of WBC depletion of the RP group.
The coagulation cascade is activated during viral infections. This response may be part of the host defense system to limit spread of the pathogen.19 A good balance between host coagulation and viral infection can improve pathological disease outcomes.20 However, excessive activation of the coagulation cascade can be deleterious. Tissue factor (TF) appears to be the major activator of the coagulation cascade during viral infection.19 Tang et al found that non-survivors of COVID-19 showed significantly higher levels of D-dimer, longer PT and APTT.We also observed a similar change. Compared with the control group, the PT and APTT of the RP group were prolonged, but there was no significant difference in FIB, ATIII, and D-dimer. This suggests that the activation of the exogenous coagulation pathway with TF as the starting point may be involved in the process of immune clearance of SARS-CoV-2,and it is milder in children. At present, there is still too much unknown, and the specific role and mechanism of the activation of coagulation cascade in SARS-CoV-2 clearance need to be further explored.
There are several limitations in our retrospective cohort study. First, due to the small sample size of the single-center research hospital, logistic regression analysis cannot be used to control confounding factors. Second, the children may be in different stages of COVID-19 when they are admitted to the hospital. Third,some children’s humoral immune function and lymphocyte subclassification data by flow cytometry are missing, which may not reflect the true difference between the two groups.Therefore,these results should be carefully interpreted owing to potential selection bias and residual confounding. Larger cohort studies from other cities in China and other countries may also be needed to provide further data support.