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Back to Journal »International Journal of General Medicine» Volume 14

Progress in the diagnosis and treatment of COVID-19 in children: a review

Authors: Wang L, Li G, Yuan C, Yang Y, Ling G, Zheng J, Zhou Y, Zhang T, Lin W, Lin Z 

Published on November 12, 2021, the 2021 volume: 14 pages 8097-8108

DOI https://doi.org/10.2147/IJGM.S335888

Single anonymous peer review

Editor who approved for publication: Dr. Scott Fraser

Wang Libo, 1 Gan Li, 1 Chang Yuan, 1 Yang Lele, 1 Gong Xialing, 1 Zheng Jinyu, 1 Zhou Yiyang, 1 Zhang Tianlei, 1 Lin Wei, 2 Lin Zhenlang 2 1 Department of Clinical Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province , People’s Republic of China; 2 Department of Pediatrics, The Second Affiliated Hospital of Wenzhou Medical University and Yuying Children’s Hospital, Wenzhou 325000, Zhejiang, China Corresponding Authors: Wei Lin; Lin Zhenlang Email [email protected]; [email protected] Abstract: Coronavirus Disease 2019 (COVID-19) It has been spread in many countries around the world and has the characteristics of long incubation period, strong infectivity, strong variability, high population susceptibility, and diverse modes of transmission. Its causative agent is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compared with adult patients, the clinical manifestations of COVID-19 in children are usually mild or asymptomatic infection, but children are also important carriers of the virus and play an important role in the spread of the virus. In addition, some children will show excessive inflammation, and serious complications such as childhood multiple system inflammatory syndrome (MIS-C) will occur. At present, the research on COVID-19 in children is not yet complete. This article will review the epidemiological characteristics, mechanism of action, variation characteristics, clinical manifestations, auxiliary examinations and treatment of children with COVID-19, with a view to providing assistance in the diagnosis, treatment and research of children with COVID-19. Keywords: children, COVID-19, mutation, clinical manifestations, treatment

SARS-CoV-2 was discovered in Wuhan, China in December 2019. 1 The disease caused by this virus is called COVID-19. COVID-19 is highly contagious. 2 It has now developed into a global pandemic, affecting more than 214 countries and regions around the world. As of July 2021, the cumulative number of confirmed cases worldwide has exceeded 190 million, and the cumulative death toll has exceeded 4 million. COVID-19 has become a major public health threat in the world today. However, even if there is a global pandemic that has caused serious global harm, the current research on COVID-19 is still imperfect, especially in the pediatric community.

Compared with adult patients, there are fewer pediatric patients, lower morbidity, milder symptoms, lower mortality (about 0-0.2%), and better prognosis. 3-5 Among pediatric infected persons, the incidence of common symptoms of COVID-19 is low. Among them, 59.9% (80% of adults) had fever; 55.9% (84% of adults) had cough; 20% (38.4% of adults) had runny nose. 6 At present, more and more evidences show that people in the pre-symptomatic stage carry a large amount of the virus, and the risk of transmission is higher than that of people in the symptomatic stage. 7,8 Asymptomatic infections have also been proven to play a role in the spread of the virus. Important role. 9 This means that COVID-19 children with mild symptoms and few symptoms are more likely to spread the virus due to misdiagnosis and missed diagnosis.10

Existing research shows that approximately 5% of people infected with SARS-CoV-2 may develop severe or critical COVID-19. 11 Some children exhibit excessive inflammation and experience MIS-C. 12,13 Children with MIS-C are characterized by persistent fever, excessive systemic inflammation, and multiple organ involvement. Many have severe gastrointestinal symptoms and symptoms similar to toxic shock syndrome (TSS), such as cardiac origin. Sexual shock and hypotension, most of which are serious, require care in the pediatric intensive care unit. 14 Therefore, it is necessary to deepen the understanding of SARS-CoV-2 infected children, increase the detection rate of COVID-19 children, and quickly identify and treat them. Children with critical symptoms such as MIS-C are an important task in today's world. This article reviews the epidemiological characteristics, mechanism of action, variation characteristics, clinical symptoms, auxiliary examinations and treatment of children's COVID-19, with a view to providing assistance in the diagnosis, treatment and research of children's COVID-19. .

Children are mainly infected through contact with people infected with SARS-CoV-2. The incubation period of the virus can be as long as 24 days. 15 The virus spreads mainly through respiratory droplets and close contact. 3 Most children with COVID-19 can excrete the virus through feces, and contact with aerosols or body fluids may also cause infections in children when feces and urine cause environmental pollution. 3,16 At the same time, there are reports that wastewater samples can cultivate viruses, which indicates that there may be water transmission routes. 17 Starting from newborns, children of all ages can be infected with COVID-19. 18 Available data indicate that the main source of infection in children is SARS-CoV-2 positive adults in the family. 19 Therefore, promptly isolate adults with a history of epidemiological exposure. Families help protect children from infection. 20 Generally speaking, compared with adults, children are less likely to transmit SARS-CoV-2,21, and children with a longer incubation period are less susceptible to SARS-CoV-2. 17 Children have fewer outdoor activities, less international travel, and the virus The infection rate may be reduced accordingly. 22 The data also shows that children under 5 years of age are less likely to be infected with SARS-CoV. -2 more than children over 5 years old, although there is no clear reason for this finding. 23 At present, the impact of caesarean section on the vertical transmission of COVID-19 is unclear. 24 SARS-CoV co-infection cases-2 are rare in newborns born to mothers infected with SARS-CoV-2 during the perinatal period. 25 However, because mothers who were infected with SARS-CoV-2 at the time of delivery are still contagious, newborns are still at risk of contracting the virus. 26 In order to protect newborns from SARS-CoV-2 infection, perinatal clinicians It is also necessary to emphasize the importance of paying attention to infection control and preventive measures for mothers infected with SARS-CoV-2 in the family, and requiring mothers and other nursing staff to meet non-infectious indicators. 26

Children are generally susceptible to SARS-CoV-2.18. However, the severity of the disease after infection is lower than that of adults. 21 In China, children account for only about 2% of all COVID-19 infections. 27 Children with underlying diseases (such as type 1 diabetes, congenital heart and circulatory abnormalities, obesity, essential hypertension, epilepsy, neuropsychiatric disorders, asthma, malnutrition, Down syndrome, etc.) have developed severe illness risk. 28-30 data shows that children with complex chronic diseases are three times more likely to suffer from serious diseases than children without chronic diseases. 31 The risk of SARS-CoV-2.32 in immunocompromised children increased by 2.89. The malnutrition of children with severe COVID-19 only slightly decreased, and was the highest among young children (under 5 years of age). 29 At the same time, the length of hospital stay is significantly prolonged in children infected with other viruses (such as adenovirus, rhinovirus, enterovirus, etc.). 33

SARS-CoV-2 is a kind of human coronavirus and belongs to the genus β-coronavirus. SARS-CoV-2 is mainly composed of membrane, envelope, nucleocapsid and spike glycoprotein (S protein), which plays an important role in the packaging of viral RNA genome and the process of viral infection. 34 SARS-CoV-2 enters the cell after binding to the cell's angiotensin-converting enzyme 2 (ACE-2) through the S protein on its surface. Therefore, the body's sensitivity to infection is related to the number of ACE-2.22 and 34. Pediatric individuals ACE2 is mainly located in type II alveolar cells, and can also be expressed in nasal mucosa, upper respiratory tract, heart, kidney and intestinal cells. 35 Therefore, children may have systemic symptoms of viral infection. 35 At the same time, ACE-2 can process angiotensin-2 into angiotensin-1, 3-7, leading to vasoconstriction, leukocyte migration, decreased expression of inflammatory cytokines, and activation. 36 Although ACE-2 is used in children with SARS-CoV -2 shows two-way regulation during infection, but more evidence shows that high expression of ACE-2 can protect patients with lung injury from the deterioration of the disease. 10,37 After the host cell is infected with SARS-CoV-2, the viral RNA is released into the cytoplasm, and the cellular mechanism is used for replication and translation. 35 The newly synthesized viral protein ns and RNA genome combine in the endoplasmic reticulum and Golgi and release cells through exosomes, 35 continuously infect new cells and cause serious tissue damage. In addition, it has been shown that transmembrane serine protease 2 (TMPRSS2) can promote the binding of S protein to ACE-2 and promote the entry of SARS-CoV-2 into host cells. 38 and androgen receptor, as the transcription promoter of TMPRSS2, can increase the expression of TMPRSS2 gene. 38 Therefore, the level of androgens in the body can regulate viral infection through the TMPRSS2/S protein. This may also be the reason for the higher admission rate of boys in the pediatric intensive care unit. 13 CD147 expressed on the surface of the cell membrane can be used as an alternative receptor for SARS-COV-2, allowing SARS-COV-2 to invade ACE2-deficient T cells, causing SARS-COV-2 infection in children, which may be SARS-COV-2 infection in children The specific treatment provides research direction. 39

Children infected with SARS-CoV-2 will produce corresponding immunopathological responses, involving innate immunity (the role of type I interferon (IFN) and pro-inflammatory cytokines) and adaptive immunity (B cells produce medium-term immune response to virus-specific antigens). And antibodies) play a key role in the elimination of SARS-CoV-2) and autoimmunity. 40 After SARS-CoV-2 infection, the immune response is regulated in both directions, and the result is affected by the degree of immune cell activation and cytokine imbalance. 41 In addition, host-specific factors also determine to a certain extent whether a person will develop a serious disease. 40

Studies have found that COVID-19 patients have immunological manifestations such as lymphopenia, antibody-dependent enhancement (ADE), and reduced or delayed interferon. Childhood lymphopenia mainly includes CD8 T cells, CD4 T cells and natural killer cells (NK). 42 SARS-CoV-2 can directly infect T cells through ACE2 expressed on T cells, leading to T cell death, and may also cause lymphocyte dysfunction by destroying the spleen and secondary lymphatic tissues of lymph nodes. 43,44 In addition, animal models indicate that lymphopenia may be due to an increase in the number of regulatory T cells. 45 B cells are now known to block ACE2 receptors by producing specific antibodies to prevent virus entry, thereby preventing SARS-CoV-2 infection. 46 However, it has been shown that the severity of COVID-19 is related to increased IgG reactivity. 47 This may be related to ADE. The specific antibodies present in humans can bind to SARS-CoV-2 virus and bind to certain FcR-expressing cells through its Fc fragment, thereby mediating virus entry into these cells and enhancing virus infectivity . 48 Interferon is an important part of antibody antiviral immunity. Among them, type I IFN (IFN-α and IFN-β) are widely expressed in humans. Viral infection can induce the production of interferon, which in turn triggers the transcription of interferon-stimulated genes, which have a variety of antiviral functions. It has been found that the type I IFN response of severe and critically ill COVID-19 patients is severely impaired (such as IFN-β loss and low IFN-α expression, low activity), which is related to the continuous blood viral load and 49 Therefore, we should monitor SARS-CoV-2 infects the immune status of children and intervenes in time to avoid pathological damage caused by immune imbalance.

In general, compared with adults, children with COVID-19 have milder symptoms and a good prognosis. On the one hand, ACE2 receptors are less expressed in children's respiratory tract cells, and some are immature, so the risk of SARS-CoV-2 infection is lower. 50,51 On the other hand, there is a phenomenon of elevated levels of physiological lymphocytes, especially the level of NK cells. In children's blood, this phenomenon persists after SARS-Cov-2 infection. 10 Therefore, pediatric patients are less affected by lymphopenia and decreased white blood cell counts. 22,52 In addition, adults and children are unlikely to experience uncontrolled immune activation, production of inflammatory cytokines (e.g., interleukin 6 (IL-6)), and anti-inflammatory cytokines (e.g., interleukin 10 (IL-6)). -10)). 10 Therefore, children with mild symptoms after viral infection and a good prognosis.

Although the prevalence and severity of COVID-19 in children are low, some pediatric patients will have serious complications similar to Kawasaki disease or TSS, namely MIS-C, and the peak of such cases often occurs in COVID- In the weeks after the 19.53 peak, 54 MIS-C cases often showed positive SARS-Cov-2 antibodies and negative RT-PCR results, so MIS-C is considered an immune-mediated post-infection syndrome. MIS-C may be explained by the abnormal immune or inflammatory response caused by SARS-CoV-2 infection. 55 The ratio of neutrophils to lymphocytes can be used as an inflammatory marker to assess the condition of COVID-19 MIS-C patients. 52 When the immune system is activated to a certain degree or even out of control, it will produce extreme immune attacks on the host. When SARS-CoV-2 further invades children, it prompts the human body to secrete interleukin 8, IL-6, IL-10, tumor necrosis factor-α and other cytokines, resulting in a cytokine storm, leading to excessive inflammation 56 Vascular endothelial damage and blood vessels Inflammation is an important pathology of MIS-C, and it may also be induced by immune complexes. 57 The high expression of S protein-IgG immune complex in children with MIS-C can cause inflammation. Structural protein binding in the blood60 This indicates that autoimmunity may be closely related to the pathological progression of MIS-C, such as myocarditis and vasculitis. In addition, the efficacy of intravenous immunoglobulin (IVIG) also supports the hypothesis that autoimmune response is involved in the pathogenesis of MIS-C. 61

Studies have shown that over time, SARS-COV-2 will produce mutations, and as the number of mutations accumulate, certain mutation characteristics will eventually dominate, leading to a mutant virus outbreak. 34 So far, there are 4 varieties recognized globally: Alpha or pedigree B.1.1.7 (UK), Beta or pedigree B.1.351 (South Africa), Gamma or pedigree P.1 (Japan/Brazil), and Delta or pedigree B .1.351 (South Africa) pedigree B.1.617. 2 (India). 62 S protein contains two subunits: S1, which contains the receptor binding domain (RBD), and S2, which mediates virus-host cell fusion. 63 The most common mutation in the viral genome is the substitution of D614G (Asp 614→Gly) in S1, which increases the affinity of the virus to the ACE2 receptor, leading to increased host susceptibility and increased transmission. 63,64

Viruses obtain more effective functions through mutation and natural selection, such as virus replication, transmission, and evasion of host defense functions. 63 Among people infected with the mutant strain, about 80% have only mild symptoms. These patients are ignored by early clinical screening. They have only mild symptoms and do not have typical early clinical symptoms, such as fever, cough, and upper respiratory tract infection. About 20% have severe symptoms of "cytokine storm". 65 Due to the recognition and binding of S protein, S protein and its RBD are expected to become vaccine targets for SARS-CoV-2.65. Neutralizing antibodies in serum are mainly directed against RBD domain motifs, and mutations will significantly affect the neutralization of antibodies. 65 Major viral mutations reduce the sensitivity of recently vaccinated individuals to neutralization of convalescent plasma. 63 Investigate emerging and rapidly spreading mutations and continuously evaluate phenotypes. Neutralization of serum after vaccination should be used to monitor vaccine efficacy. High priority for impact. 63 There are data showing that the sensitivity of SARS-CoV-2 mutants in some patients to plasma antibody neutralization during the recovery period is reduced by 5 times. 63 In addition, the D614G mutation does not affect the virus replication or viral particle infectivity in Vero E6 cells, but the infectivity and stability of SARS-CoV-2 produced by the human lung cell line after the mutation increase, and the D614G mutation may change the spikes The conformation of the protein thus affects the neutralization of the monoclonal antibody in an epitope-specific manner. 66 There is increasing evidence that long-term SARS-CoV- will have immune escape mutations and a variety of fast-spreading mutations. 2 Infection. 63 We should pay attention to these mutations and mutations in these infections and study them accordingly. 63

Within 5 weeks of the first discovery of the Delta variant, the main virus variant in Mesa County, Colorado was the Delta variant, which is now the main variant in the United States. 67 The county’s intensive care unit admission rate and case fatality rate suggest that infection with the Delta variant may lead to more serious outcomes. 67 Although the vaccine can reduce the transmission potential of SARS-CoV-2 and reduce the risk of human infection with the virus, Delta variants can affect the effectiveness of the vaccine and may increase 68 Although the specific mechanism of action of the variant on the vaccine has not been elucidated, more importantly, Compared with Alpha variants, the ability of antibodies to neutralize Delta variants is reduced, and Delta variants are more infectious and weaken the body's immune protection 10 times. 69 But in most cases, the level of neutralizing antibodies induced by the vaccine is sufficient to protect.69 In order to prevent the further emergence of immune escape variants, a comprehensive global vaccination and prevention strategy is needed to reduce the spread of SARS-CoV-2,63. This is the safest and most controllable way to prevent COVID-19.35. Frequent contact with grandparents and measures to vaccinate children can help reduce the possibility of SARS-CoV-2 being transmitted to the elderly. 70 On the other hand, children's vaccination helps them return to school and return to normal life. 71 Given the evolutionary nature of the SARS-CoV-2 genome, drug and vaccine developers should continue to be vigilant against the emergence of new variants or substrains of the virus. 64 Recent data indicate that some vaccines are less resistant to the B.1.351 variant, which requires 63 However, the reduced sensitivity of antibodies to the new variant does not prove that the vaccine is less effective. 63

Mild or asymptomatic infection is the main clinical manifestation of pediatric patients, mainly manifested as fever, sore throat, shortness of breath and pneumonia. 72 Compared with adults, vomiting and diarrhea are more common in pediatric patients, and the incidence of fever and pulmonary symptoms is higher than in adults. Lower, 22 and less common smell and taste. 73 Children with cancer, children receiving hematopoietic cell transplantation, children receiving solid organ transplantation, and other children taking immunosuppressive agents, mostly suffer from asymptomatic or mild gastrointestinal symptoms due to weakened immune function and weakened immunity. Reactions after infection with COVID-19, 32, and 74 have a low risk of death. 75 The frequency and mortality of dyspnea and mortality in hospitalized immunocompromised adults may be due to their complications (such as hypertension, cardiovascular disease, and diabetes). 32 Children infected with SARS-CoV-2 have relatively few neurological complications. 76 Neurological symptoms are mainly non-specific symptoms such as headaches. The incidence of severe symptoms and specific complications is only about 1%. 76 This also causes children with unobvious respiratory symptoms to be easily misdiagnosed and missed. 77 Severe infections may cause acute respiratory distress syndrome, septic shock, metabolic acidosis and coagulopathy. 22 The results of the study showed that the length of hospitalization and intensive care, lymphocytosis, and abnormal CT findings (ground glass and consolidation) of children in the area. Critical recombination is higher than non-critically ill children and is the most reliable factor related to the severity of COVID-19.78

Some children with progressive diseases may have serious complications of MIS-C. Complications are particularly prominent in cardiovascular disease, and their clinical manifestations are similar to the symptoms of macrophage activation syndrome, staphylococcal and streptococcal TSS, and sepsis. 79 Other systems are also affected, including the respiratory system (for example, manifestations of respiratory distress), urinary system (for example, anuria, oliguria), blood system (for example, active bleeding and thrombosis), digestive system (for example, diarrhea, liver Involvement), nervous system (such as irritability, confusion), etc. 13 Compared with children without MIS-C, children with MIS-C have fewer sore throats and respiratory symptoms, inflammation (such as fever and rash), and gastrointestinal (such as vomiting and diarrhea) symptoms. 72 In addition, rare neurological complications in children infected with SARS-CoV-2 are particularly likely to occur in children with MIS-C infected with SARS-CoV-2, among which encephalopathy is more common and sometimes accompanied by transient symptomatic epilepsy Onset, but no long-term neurological sequelae. 76 Therefore, any child with primary neurological symptoms, fever and mild or no respiratory symptoms in COVID-19 endemic areas should be considered as one of the clinical manifestations of MIS-C. In addition, serum albumin levels 13 and croup80 can also be used as predictive indicators of MIS-C for close monitoring. Since most children with MIS-C have mild or no symptoms when initially infected with COVID-19, a high degree of vigilance is required for MIS-C.81

Chest computed tomography (CT) can be used for screening and diagnosis of COVID-19 infection, showing the progress of the disease, and has broad prospects in the application of adult symptom screening. 82,83 However, because the clinical symptoms of COVID-19 children are relatively mild, CT is difficult to detect, and CT produces high-dose radiation, pediatricians should propose the necessity of chest CT based on clinical needs. 83 The most common CT abnormalities in children with COVID-19 pneumonia are peripheral and/or subpleural mixed ground glass shadows and consolidation. 84 Among children with abnormal CT scans, more than half of them can see the "halo" sign, that is, focal consolidation, surrounding ground glass shadows, thickening of the bronchial wall and more peribronchial opacity. Children are more common in adults. 84 If there are multiple lobular lesions in the lungs of a child, and the lungs of the child are white, it indicates a higher inflammatory response. 82 After active treatment, the chest X-ray and CT findings of 82 infants are not typical, and further research and summary are still needed. 82

86.4% of pediatric patients with COVID-19 infection can be correctly diagnosed by lung ultrasound (LUS). 85 In the absence of reliable and highly sensitive diagnostic tests or excessive requests for nasal swabs, LUS can be used to diagnose children with suspected COVID-19 and persistent cough, because ultrasound can highlight the interstitial lung lesions caused by COVID-19 and can be used to enhance The ability to diagnose children with suspected COVID-19 pneumonia. 86 The standardized LUS protocol combines the ultrasound probability mode with the clinical phenotype. The LUS high probability mode and the LUS medium probability mode are very sensitive to rule out interstitial pneumonia. When the child's clinical symptoms worsen, the sensitivity increases. 87 During the COVID-19 pandemic, LUS can quickly identify with or without COVID-19 pneumonia infection, and help clinicians quickly guide children to manage and use hospital resources. 87 On the other hand, although CT is the gold standard for pneumothorax assessment, it is critically ill. Patients are restricted by inconvenient transportation and high doses of radiation88. Exposure to ionizing radiation has therefore become an effective aid for diagnosing pneumothorax during follow-up of SARS-CoV-2.88 children after diagnosis. However, there are still reports showing that 45% of individuals who misdiagnose COVID-19 by LUS are not infected. Therefore, it is necessary to use LUS rationally in clinical practice. 85

Timely diagnosis of children infected with SARS-CoV-2 is not only important for individuals, but also essential for reducing the spread of the virus during a pandemic. 89 Abnormal results of COVID-19 laboratory tests in children are less common than in adults. Ninety cases of lymphopenia are very common in adults with COVID-19, and only 5.5% of children have this test result. 90 Children are unlikely to have leukopenia, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), alanine aminotransferase levels, lactate dehydrogenase levels, and aspartate aminotransferase levels are not significantly increased High, and the level of creatine phosphate isoenzymes tends to increase significantly. 90 Most children have normal levels of procalcitonin, the number of D-dimer and ferritin in the blood increases in critically ill children, and the number of lymphocytes gradually decreases. 3 The number of neutrophils in children with ordinary COVID-19 can be reduced, but the number of white blood cells in children with severe neu disease is significantly increased. 52 For example, in children with progressive inflammation, they often experience lymphopenia, hypoalbuminemia, hypertriglyceridemia, and elevated IL-6, ESR, lactate dehydrogenase, CRP, and fibrin Pro, procalcitonin, D-dimer, 13 bilirubin and liver enzyme levels can be used to diagnose the severity of childhood diseases. 22 In short, SARS-COV-2 can cause abnormal hematology parameters in children, which are different from adult examination results. This discovery is conducive to the early diagnosis and treatment of COVID-19 in children.

If necessary, membrane lung oxygenation can be taken according to the situation of the child. 3 For children with high fever, convulsions or epileptic seizures, the corresponding drugs should be used to control the condition and ensure that the airway is unobstructed before treatment. 3

Antiviral drugs (such as Remdesivir) can be used to treat critically ill or critically ill children (age ≥ 12 years, weight ≥ 40 kg) that require oxygen inhalation, or invasive mechanical ventilation or extracorporeal membrane oxygenation. 92 COVID-19 monoclonal antibody therapy is not recommended for children, but infliximab can effectively treat children's Crohn's disease and prevent children's systemic inflammatory response. 93 Other drugs, including chloroquine, hydroxychloroquine, azithromycin, or lopinavir/ritonavir are also not recommended for the treatment of COVID-19. 92 Drug development focuses on the target of virus entry into the host and the RNA polymerase that is dependent on viral RNA. 94 Due to the emergence of SARS-CoV-2 variants, effective broad-spectrum antiviral drugs against SARS-CoV-2 and their variants need to be studied, such as targeting the fusion inhibition of the conserved heptapeptide repeat region 1 in the S2 subunit of the S protein Agent. 95

Traditional Chinese medicine is based on syndrome differentiation and treatment. 96 Through the analysis of symptoms and prescriptions, COVID-19 can be prevented, embodying the concept of "prevention and treatment", with comprehensive anti-virus, anti-inflammatory, immune regulation and organ protection. 96 It can increase the cure rate, delay the course of the disease, reduce the mortality rate, and treat COVID-19. 96 In terms of prevention, herbal flavors, Chinese herbal decoctions, moxibustion, diet therapy, herbal medicines can be used to replace tea, and Chinese herbal foot baths can be used to cut off the route of transmission. 97,98 In the treatment of Chinese medicine, Chinese medicine decoctions and Chinese patent medicines can be used for treatment, and the corresponding Chinese patent medicines can be used. 97 At the same time, acupuncture therapy can regulate the human immune system, and different acupoints are used for different clinical symptoms. ges.97 Acupuncture is expected to become a safe and effective adjuvant therapy. 97 According to reports, the integration of traditional Chinese and Western medicine can shorten the treatment time of COVID-19 patients, increase the clinical cure rate, and play a huge role in fighting the epidemic. The COVID-19 pandemic. 99 Since the disease spectrum of children is different from that of adults, the effectiveness and safety data of Chinese medicine in treating children are not comprehensive. This method needs further research. 100

Vitamin C has the potential to control inflammation, but there is no evidence that vitamin C supplementation can effectively reduce the risk of SARS-CoV2 infection. 101 Vitamin D can prevent or treat SARS-CoV2 infection by improving SARS-CoV2 infection. 102 Folic acid is also a potential treatment for COVID-19.103. Androgens can promote the entry of COVID-19 virus into host cells. TMPRSS2 inhibitors or ACE2 receptor binding competitive inhibitors are effective ingredients to prevent new coronaviruses. Therefore, it is possible to treat COVID-19 by inhibiting androgens, while bromhexine, a drug with both good and safe properties, is Provide clinicians with better treatment strategies, and specific treatments are still under study. 104

Support for intensive care, immunomodulation (steroids and intravenous immunoglobulin) and organ support therapy (including hemodynamic support) are effective for children with MIS-C. 55 In the pediatric MIS-C treatment consensus, intravenous immunoglobulin is recommended as the first-line treatment, corticosteroids as the second-line drug, and anticoagulants should be used according to the child's condition. 105 At present, the most widely recommended is intravenous immunoglobulin drugs. 106 This drug helps restore the contractile function of the left ventricle. 107 In addition, the length of the treatment of MIS-C with corticosteroids has shortened the length of hospital stay in children. 108 For example, low-dose prednisolone can shorten the hospital stay of children with moderate to severe COVID-19.109. 109 Cases of MIS-C have recovered completely after oral steroid therapy alone. 110 Another report also indicated that children with MIS-C who have cars have a lower risk of cardiovascular dysfunction. Compared with IVIG treatment alone, IVIG combined with corticosteroids in the treatment of diabetic renal insufficiency 111 takes shorter time to restore heart function. 112 However, because corticosteroids may slow down virus clearance and increase the risk of infection in children, the optimal dose and duration of corticosteroid treatment in children with MIS-C are not yet clear. 113 Therefore, corticosteroids should be used cautiously based on the child's clinical condition.

Children with low immune function mainly include: children with congenital immunodeficiency, children with acquired immunodeficiency caused by immunosuppressive therapy, and children with immune dysfunction caused by related chronic diseases (such as organ dysfunction or failure or severe inflammatory diseases). 114 Immunosuppression appears to be a protective factor that reduces the risk of critical illness in children with weakened immune functions. 115 Therefore, children treated with long-term immunosuppressive agents should maintain a certain dose of immunosuppressive agents to prevent the recurrence of the underlying disease. On this basis, antiviral treatments for children with weakened immune systems can control the virus invasion and improve the prognosis of children. 75,115 For children who do not respond to antiviral therapy, IVIG has shown a good effect, and there are no obvious complications for the time being. 115 Moderate anti-inflammatory therapy can also be tried for children with progressive pneumonia (such as anti-IL-6 or corticosteroids). 116 In conclusion, the treatment of immunocompromised children should be determined based on their clinical manifestations. 117

Blood purification therapy can be used to remove inflammatory factors and block the "cytokine storm"; bronchoscopy and lavage can ensure normal airway ventilation and prevent obvious airway obstruction; 3 using convalescent plasma therapy to treat severely ill children is safe and effective Yes, 118 and there is evidence that this therapy does not increase the risk of thromboembolism in children with COVID-19;119 Appropriate antibiotics (such as azithromycin) can be used to control secondary bacterial infections. 120

COVID-19, Coronavirus Disease 2019; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; MIS-C, Childhood Multiple System Inflammatory Syndrome; TSS, Toxic Shock Syndrome; S Protein, Spike Sugar Protein; ACE-2, angiotensin converting enzyme 2; TMPRSS2, transmembrane protease serine 2; interferon, interferon; ADE, antibody-dependent enhancement; NK, natural killer; IL-6, interleukin-6; IL-10 , Interleukin-10; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RBD, receptor binding domain; CT, computed tomography; LUS, lung ultrasound; Chinese medicine, traditional Chinese medicine; IVIG, intravenous immunoglobulin.

As a special group, most children with COVID-19 are asymptomatic or mild. They are less affected by the COVID-19 pandemic, but children are also important carriers of the virus, and they may also be misdiagnosed due to missed diagnosis or have serious complications. Sick and die. For most children with COVID-19, only general supportive therapy is sufficient. However, for critically ill children with severe complications such as MIS-C or patients with underlying immune function, after comprehensive evaluation, rational use of IVIG, steroids, and antiviral therapy can reduce the occurrence of serious hemodynamic complications and improve the risk. The prognosis of severely ill patients. children. The current research on children infected with SARS-CoV-2 is still incomplete, and there are still few drugs available. Clinicians should maintain a high degree of vigilance for children who are at risk and potential symptoms of SARS-CoV-2, pay attention to the clinical diagnosis, treatment and prognosis of pediatric COVID-19 patients, and reduce the risk of virus transmission due to missed diagnosis. Diagnose and reduce the mortality rate of pediatric COVID-19.

Wei Lin and Zhenlang Lin made equal contributions to this work and should be considered as co-corresponding authors.

The authors report no conflicts of interest in this work.

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