Diagnosis,treatment and prevention of severe acute respiratory syndrome coronavirus 2 infection in children: experts’ consensus statement updated for the Omicron variant

Rong-Meng Jiang·Zheng-De Xie·Yi Jiang·Xiao-Xia Lu·Run-Ming Jin·Yue-Jie Zheng·Yun-Xiao Shang ·Bao-Ping Xu·Zhi-Sheng Liu·Gen Lu·Ji-Kui Deng·Guang-Hua Liu·Xiao-Chuan Wang ·Jian-She Wang·Lu-Zhao Feng·Wei Liu·Yi Zheng·Sai-Nan Shu·Min Lu·Wan-Jun Luo·Miao Liu ·Yu-Xia Cui·Le-Ping Ye·A-Dong Shen·Gang Liu·Li-Wei Gao·Li-Juan Xiong·Yan Bai·Li-Kai Lin ·Zhuang Wei·Feng-Xia Xue·Tian-You Wang·Dong-Chi Zhao·Jian-Bo Shao·Daniel Kwok-keung Ng ·Gary Wing-kin Wong·Zheng-Yan Zhao·Xing-Wang Li·Yong-Hong Yang,·Kun-Ling Shen,

It has been more than 3 years since the novel coronavirus(SARS-CoV-2) pandemic raged globally.The coronavirus disease 2019 (COVID-19) has greatly influenced human society.According to data from the World Health Organization (WHO),there were over 656 million confirmed cases of COVID-19 in the world as of January 1,2023,including over 6.6 million deaths [1].In the first year of the SARS-CoV-2 pandemic,the epidemic strains were mainly the original strain,Alpha,Beta,and Gamma variants spreading all over the world.The Delta variant has taken dominance after December 2020.Since November 2021,the Omicron variants,including B.1.1.529,BA1,BA2,BA4,and BA5 variants have emerged with increased infectivity,shortened incubation period,and enhanced immune escape ability,but decreased pathogenicity,resulting in a new round of global epidemic outbreak,and a significant increase in the infection rate of children.Since October 2022,the Omicron subvariants,such as BF.7,BQ.1,and BQ.1.1,as well as the recombinant strains (XBB) with stronger immune escape ability and infectious ability have increased rapidly,and have replaced BA.5.2 as the dominant variants in several countries and areas.According to the surveillance data of the Chinese Center for Disease Control and Prevention,the current circulating strains in China are mainly BA.5.2 and BF.7,which are the sub-lineage of BA.5 [2].

Currently,SARS-CoV-2 vaccination has been widely used worldwide,and has played an important role in reducing the rate of hospitalization and the mortality of severe and critical cases.The coverage rate of the f irst dose of vaccine and full dose for children over 3 years old in China has reached above 98% and 95%,respectively [3].Due to the diff erences in regional vaccination rates and individual genetic factors,the occurrence of infection and severe disease cannot be completely prevented.The increase in febrile convulsion,acute necrotizing encephalopathy (ANE),multisystem inf lammatory syndrome in children (MIS-C),and psychobehavioral abnormalities in children after SARSCoV-2 infection have attracted high attention.

At present,the Omicron variant has become the world's main circulating variant.In order to guide the treatment of SARS-CoV-2 infection in children with the times,the updated Expert Consensus on the Diagnosis,Treatment,and Prevention of Novel Coronavirus Infection in Children is specially formulated for clinical reference,with reference to the 10th edition of the diagnosis and treatment protocol for COVID-19 jointly issued by the National Health Commission and the National Administration of Traditional Chinese Medicine,the Expert Consensus on the Diagnosis,Treatment and Prevention of Novel Coronavirus Infection in Children (4th Edition) and the diagnosis and treatment strategy of pediatric-related viral infections [4,5].

Etiology

SARS-CoV-2 belongs to the β-coronavirus genus [4,5].The viral particles are round or oval in shape,60-140 nm in diameter with an envelope.The virion contains four structural proteins: spike protein (S),envelope protein (E),membrane protein (M),and nucleocapsid protein (N).The genome of SARS-CoV-2,a 29.9 kb single-stranded RNA,is coated by N protein and forms the nucleocapsid,which is enveloped by a lipid bilayer with viral S,M and N proteins embedded.Angiotensin converting enzyme-2 (ACE2),as the cell surface receptor,can be recognized and bound by the receptor-binding domain (RBD) of virus S protein and assist the virus to enter and infect the host cells.The genetic mutations occur frequently during SARS-CoV-2 circulating.Recombination may emerge when diff erent variants or lineage of SARS-CoV-2-infected human body at the same time.Certain mutations or recombination can aff ect the biological characteristics of the virus.For example,the mutation of specif ic amino acids on the S protein leads to enhanced affi nity between SARS-CoV-2 and ACE2,and enhanced intracellular replication and transmission.Some amino acid mutations in S protein can also increase the immune escape ability to the vaccine and reduce the cross-protection ability between diff erent variants,leading to breakout infection and a certain percentage of reinfection.According to current relevant data,the variants that have the greatest impact on humans include: Alpha B.1.1.7,Beta B.1.351,Gamma P.1,Delta B.1.617.2 and Omicron B.1.1.529 [4,5].The Omicron variants have become the predominant infective strains worldwide,including BA.1,BA.2,BA.3,BA.4,BA.5,XE,XF,XD,XBB lineage and BQ.1 sub-lineage (belongs to BA.5 lineage),in which XE (BA.1/BA.2 recombinant),XF (BA.1/ Delta in England recombinant),XD (BA.1/Delta variant recombinant) and XBB (BA.2.10.1/BA.2.75 recombinant) are recombinant strains [6-9].The BQ.1 and XBB lineage have been detected in China,however,BA.5.2 and BF.7 remain the main epidemic strains [2].Comparing with the original strain,the Omicron variant has more than 34 mutations in the RBD of S protein,which enhanced the transmissibility and immune escape capability with the basic reproduction number (R0) of 9.5 (R0 of the Delta variant is 3.0).BA.4/5 variants have L452R,F486V and R493Q mutations,which are the key mutation sites leading to its high immune escape ability [10].Thus,it is necessary to keep monitoring genetic mutations or the emergence of new mutants of SARS-CoV-2,and the changes in their biological characteristics.

The survival time of SARS-CoV-2 on diff erent object surfaces is quite diff erent.Under normal temperature conditions,SARS-CoV-2 can survive for 3 to 16 h in aerosol,3 to 4 days in stainless steel and plastic surfaces,1 to 2 days in cardboard and banknotes,but only about 30 min in tissue paper,and at least 30 min in the air of poorly ventilated buses [11,12].SARS-CoV-2 can survive much longer in cold environments.For example,the viral concentration was reduced by only 0.7 log TCID50/ mL (about 10%) within 14 days at 4 ℃ [13].Comparing with other SARS-CoV-2 variants,the Omicron variants (BA.1 and BA.2) have better environmental stability [14].The virus is sensitive to ultraviolet rays and heat,so it can be inactivated at 56 °C for 30 min,as well as ether,75% ethanol,chlorine disinfectant,peracetic acid,chloroform,and other fat solvents,except chlorhexidine.

Epidemiology

Source of infection

The main source of infection is SARS-CoV-2-infected persons (including symptomatic persons and asymptomatic persons).The symptomatic persons are infectious in the incubation period,and the infectivity is the strongest within 3 days after the onset.Asymptomatic persons are important infectious sources that are not easy to be found [4,5].

Transmission route

(1) Respiratory droplets and close contact are the main routes of transmission.(2) Aerosol transmission can occur in a relatively closed environment.(3) Infection can also happen through contacting with contaminated articles.(4)Vertical transmission of SARS-CoV-2 from mother to child has been reported,which is only found in late-pregnancy infectious cases [4,5].

The main characteristic of SARS-CoV-2 infection in children is the clustering of incidence in families,schools and nurseries.

Susceptible population

Children are generally susceptible to SARS-CoV-2,and those with underlying diseases (congenital heart disease,chronic lung disease,nervous system disease,severe malnutrition,tumor,obesity,diabetes,genetic diseases,congenital and acquired immunodef iciency or immunocompetent) are prone to severe diseases.Certain immunity can be acquired from vaccination or past infection [4,5].

Seasonal characteristics

SARS-CoV-2 infection can occur all year round.UV rays and high temperatures can reduce its transmission to some extent.Therefore,in summer,there is a relatively low incidence of SARS-CoV-2 infection,whereas the incidence increases in autumn and winter [4,5].

Pathogenesis

The main pathogenesis of SARS-CoV-2 is related to the direct damage of the virus,excessive immune response of the host and host genetic factors.The details are as follows.

Direct damages caused by virus

SARS-CoV-2 can bind to ACE2 receptors of respiratory epithelial cells,kidney,heart,intestine,brain,vascular endothelium,immune cells and other human cells,directly causing organ damage [15-17].SARS-CoV-2 insults the intestine epithelium and disturbs the gut micro-environment,which leads to diarrhea,vomiting and poor appetite;it can insult neural cells via synaptic or blood transmission,which leads to headache,dizziness,encephalitis and encephalomyelitis.The Omicron variants showed a marked degree of mutation including S-pro mutation and non-S-pro mutation,as compared with the previous SARS-CoV-2 variants.S-pro mutations enable the virus to utilize the plasma membrane and endosomal pathways for virus entry,and are more likely to insult the respiratory tract [18-20].Compared with the wildtype SARS-CoV-2,the mutation of S protein and its RBD site of Omicron variant makes it have higher affi nity with ACE2 and stronger immune escaping ability,so it is more infectious,and the neutralization activity against Omicron variant induced by SARS-CoV-2 vaccine and therapeutic monoclonal antibody is greatly reduced [6].

Damages secondary to excessive immune responses

(1) Cytokine storm,excessive immune response to infection,is characterized by activation and infiltration of immune cells (monocytes,T helper cells,cytotoxic T cells,etc.) and secretion of proinf lammatory cytokines including TNF-α,IL-1,IL-6,IFN-α,-β and -γ,which induce a systematic inf lammatory response and autoimmune response[21,22].(2) The clotting cascade can be activated by coagulation disorders,vascular injury and secretion of cytokines,resulting in coagulation/f ibrinolytic system disorders,mediating thrombosis,and aggravating multi-organ damage.Multisystem inf lammatory syndrome in children(MIS-C) is also related to abnormal immune response and diff used vascular injury after SARS-CoV-2 infection [23].

Host genetic factors

Among severe or fatal cases,3-5% of them have genes defects in Type I IFN pathway,including TLR3,IRF7 and IRF9;and 10-20% of severe or fatal cases have anti-IFN antibodies,leading to endogenous def iciency of IFN [24,25].

Pathological changes

The respiratory system is the most frequently aff ected system.Desquamation,congestion and oedema of respiratory epithelial cells are caused by virus invasion.Increased airway mucus secretion and formation of mucus plug in the airway lumen,resulting in narrowing of the airways.The lesion can involve the alveolar cavity and appear as type II alveolar epithelial cell hyperplasia,some cells are shed,serous,f ibrin exudate and hyaline membrane are formed in the alveolar cavity,with mononuclear and macrophage exudation,diff use alveolar damage,which can lead to respiratory distress.The alveolar septum is hyperemia and edema;mononuclear cell and lymphocyte inf iltration and intravascular transparent thrombosis can be seen.Organizing pneumonia,pulmonary infarction,pulmonary hemorrhage,f ibrosis,and other pathological manifestations may appear [26-33].

Additionally,the digestive tract,liver,spleen,pancreas,kidney,heart,brain,lymph nodes,skin,and other organs can also be aff ected,causing tissue and cell damage,in which SARS-CoV-2 nucleic acid can be detected.Endothelial cell exfoliation and intimal or whole-layer inf lammation are observed in small vessels at the site of infection.Intravascular mixed thrombosis,thromboembolism and infarction at corresponding sites can be seen.Microvessels of major organs (lung,liver,etc.) show hyaline thrombus formation,such as extensive alveolar capillary microthrombus [26-33].

Clinical manifestations

The incubation period ranges from 1 to 14 days,mostly 2-4 days.The clinical manifestations are diverse,children mainly manifest mild symptoms,and the prognosis for most children is generally good without any long-term sequelae[4,5,34,35].

Systemic manifestations

Symptoms mainly include fever,fatigue,and muscle soreness.Some children may have a high fever,usually lasting no more than 3 days.

Respiratory symptoms

Respiratory manifestations commonly include cough,nasal congestion,runny nose,sore throat,and so on.Children may have acute laryngitis,acute laryngotracheitis,presenting with hoarseness,barking cough,and respiratory distress with or without aspiratory laryngeal ringing and upper airway obstruction.Those with pneumonia may develop shortness of breath and wheeze,and their lung auscultation may indicate wet rales and wheezes.Severe disease may progress to dyspnea and cyanosis,and only rare cases will progress rapidly to acute respiratory distress syndrome,septic shock,diffi cult-to-correct metabolic acidosis,and multiple organ failures such as acute kidney injury or renal failure.

Digestive tract system manifestations

Some young patients show decreased appetite,vomiting,diarrhea,as well as other digestive tract symptoms.

Neurological and psychiatric manifestations

Non-specific neurological symptoms such as headache,irritability of myalgia,and decreased olfaction or taste may occur.Few children will be presented with specif ic neurological involvement,including convulsive episodes,encephalopathy,encephalitis or meningitis,acute disseminated cerebrospinal meningitis,cerebrovascular disease,Guillain-Barre syndrome,and so on.Children with underlying nervous system diseases or those who have not been vaccinated are prone to develop severe neurological diseases in the acute stage,which can be life threatening.An extremely small number of cases can rapidly progress into COVID-19-related encephalopathy like ANE after infection,and the clinical manifestations include acute encephalopathy symptoms such as convulsion after fever,disturbance of consciousness (rapid progression to coma),multiple organ failure,and even death in severe cases.

In addition,few cases may have abnormal sleep,cognitive dysfunction,anxiety,depression,and impulsive aggressive behavior.Severe cases may appear with acute or chronic psychological stress reactions.

Circulatory system manifestations

Some cases may present with increased heart rate or arrhythmia,or only with pale/bluish,cyanosis,poor mental response,and chest tightness.In severe cases,the onset of the disease is rapid,which can be easily ignored due to hidden symptoms,and rapidly progresses to acute heart failure,and malignant arrhythmia.Very few children may suff er from fulminant myocarditis or cardiogenic shock,or even sudden death.

Skin manifestations

Some children will develop a rash accompanied by fever or after the fever has subsided.The types of rashes are diverse and can be presented as acute urticaria,maculopapular (measles-like) lesions,erythema multiforme,and so on.

COVID-19-related MIS-C

The manifestations of MIS-C are as follows: fever (＞ 38 ℃)lasting for more than 3 d,with two or more of the following signs of systemic involvement,including (1) rash or bilateral non-suppurative conjunctivitis or cutaneous mucositis (mouth,hands,or feet);(2) hypotension or shock;(3)myocardial dysfunction,pericarditis,valvulitis,or coronary artery abnormalities;(4) coagulation disorders;(5) acute gastrointestinal symptoms (diarrhea,vomiting,or abdominal pain) except for shock syndrome caused by other microbial infections.

Laboratory examinations

Hematology examination

(1) Peripheral blood leukocyte counts are normal or reduced,with decreased lymphocyte count;C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR) are increased,while procalcitonin (PCT) is usually normal.Liver enzymes,lactate dehydrogenase,muscle enzymes,myoglobin,creatinine,ferritin and troponin are increased in very few children.(2) In severe and critical cases,the D-dimer increased and the number of peripheral blood lymphocytes decreased progressively.A higher level of inf lammatory factors may be detected,such as IL-1,IL-6,IL-8 and TNF-α.(3) In MIS-C cases,inf lammatory indexes (CRP,ESR,PCT,ferritin and IL-6) increased signif icantly,neutrophils increased,lymphocytes decreased,D-dimer,troponin and B-type natriuretic peptide increased[36,37].

Pathogen analysis

Nucleic acid detection

Nucleic acid of SARS-CoV-2 can be detected in specimens such as nasopharyngeal (oropharyngeal) swabs,sputum and other lower respiratory tract samples,blood,and cerebrospinal f luid.Real-time PCR is the most common method for detection of SARS-CoV-2 nucleic acid [4,5].

Antigen test

Antigen test of respiratory tract samples for SARS-CoV-2 is simple and rapid,which is suitable for the outpatient,emergency department and self-detection.The sensitivity of antigen test is lower than that of nucleic acid test,therefore,SARSCoV-2 infection cannot be excluded by a negative result of antigen test [4,5,38].

Virus isolation

SARS-CoV-2 can be isolated from the respiratory tract and other samples.

Serological antibody detection

(1) For patients who have received SARS-CoV-2 vaccine,it is not recommended to use SARS-CoV-2 antibody detection to diagnose SARS-CoV-2 infection.(2) For unvaccinated patients,the positive of serum IgM and IgG antibodies against SARS-CoV-2 are helpful for diagnosis of SARS-CoV-2 infection.Non-specif ic reactions must be ruled out for positive IgM antibody detection.The negativity of both IgM and IgG antibodies at the early stages of the disease cannot exclude SARSCoV-2 infection,because it takes a certain period for the body to produce serum-specif ic antibodies and reach the detection threshold after virus infection.IgM and IgG tests are of limited value in the early diagnosis of SARS-CoV-2 infection and are suitable for retrospective diagnosis and seroepidemiological investigation [4,5].

Radiographic examination

Chest imaging examination

Radiographic examination is generally not necessary for asymptomatic SARS-CoV-2 infected patients and those who only manifest with acute upper respiratory tract infection.Chest X-ray or computerized tomography (CT) examination should be taken if lower respiratory tract infection symptoms are signif icant or persistent,or abnormal signs in the lungs are discovered by physical examinations [35,39-45].

Chest X-ray scan

Localized patchy shadows may appear in chest x-ray scans.Bilateral multiple solid shadows or “white lungs” exhibition can be found in severe cases.

Chest CT scan

At early stage,mostly single or multiple limited groundglass opacity (GGO) will be shown in CT scanning,shaped like thin mist or fine grid,with thickened blood vessel shadows inside,and few will exhibit limited solid shadows.Then,the progression of the disease can be manifested as increased GGO,or enlargement of scope with a merging trend,and then become a large solid shadow.In severe cases,diffuse consolidation and GGO will mix-existed in unilateral or bilateral lungs,with air bronchogram inside.Mostly,they are manifested with solid shadows,only a few will become "white lungs",and pleural effusion and pneumothorax are rare.In the majority of cases in children,the pulmonary lesions can be completely absorbed and recovered,and interstitial fibrosis is rarely seen [35,39-45].

Cranial imaging examinations

Head Magnetic Resonance Imaging (MRI) is preferentially taken when the young patient is highly suspected of serious central nervous system damage,especially ANE,and the head CT should be performed for the patients who cannot obtain MRI.

The imaging features of ANE mainly contain symmetrical and multifocal brain lesions,with both white matter and gray matter involved.The lesions are mainly distributed in the thalamus (100%),tegmental tegmentum of the superior brainstem,periventricular white matter,and cerebellar medulla.The typical manifestation of cephalic MRI includes a "trichromatic pattern" (central high signal and peripheral low signal ring,and peri-thalamic high signal) or a “bicolor pattern” (central low signal and peripheral high signal) in the thalamus on apparent diff usion coeffi cient (ADC) plots.Cerebral edema manifestations will be shown in the early stages,and spotty bleeding and necrosis will appear when it worsens.Most surviving cases may retain degenerative changes such as cerebral atrophy,hemosiderin deposition,and cystic cavity formation,which can last for months to years [35,39-45].

Diagnosis

The diagnosis is made based on the comprehensive analysis of epidemiological history,clinical manifestations and laboratory f indings.A positive nucleic acid detection of SARSCoV-2 is the primary diagnostic criteria.

Diagnostic criteria

(1) Clinical manifestations related to SARS-CoV-2 infection.(2) One or more of the following etiological or serological tests are available: ①SARS-CoV-2 nucleic acid test is positive.② SARS-CoV-2 antigen testing is positive.③SARSCoV-2 isolation is positive.④the titer of specif ic antibody IgG in serum during the recovery phase is fourfold or higher than that in the acute phase [4,5].

Clinical classif ication

Asymptomatic infection

The pathogenic test for SARS-CoV-2 in specimens such as respiratory specimen is positive,and without relevant clinical manifestations,such as fever,dry cough,sore throat and other symptoms and signs that could be perceived or recognized clinically [4,5,46].

Mild cases

The clinical manifestations are mainly characterized by symptoms of acute upper respiratory tract infection,such as cough,sore throat,nasal congestion,etc.,which may be accompanied by fever,fatigue,headache,myalgia,etc.There are no clinical and physical signs of lower respiratory tract involvement [4,5,46].

Moderate cases

Children have respiratory symptoms such as cough and shortness of breath,but respiratory rate (RR) is ＜ 30 times/min,and oxygen saturation is ＞ 93% under a resting state.Chest imaging indicated changes of viral pneumonia,but not reaching the criteria of severe pneumonia [4,5,46].

Severe cases

Those who meet any of the following criteria are severe cases.(1) Respiratory rate: ≥ 60 times/min(＜ 2 months),≥ 50 times/min (2-12 months),≥ 40 times/min (1-5 years),≥ 30 times/min (＞ 5 years) (after ruling out the eff ects of fever and crying).(2) Finger oxygen saturation is ≤ 93% when air is inhaled in the resting state(3) Dyspnea: assisted breathing (moans,nasal f laring,and three concave signs),cyanosis,intermittent apnea.(4) Disturbance of consciousness or convulsion.(5) Food refusal or feeding diffi culty,with signs of dehydration.(6) Pulmonary high-resolution CT (HRCT) examination showing bilateral or multi-lobe inf iltrates,and rapid progression of disease (＞ 50%) in a short period or with pleural eff usion[4,5,46].

Critical cases

Those who meet any of the following criteria are critical cases: (1) Respiratory failure requiring mechanical ventilation;(2) Shock;(3) Combined with acute encephalopathy,ANE or severe dysfunction of other organs require intensive care [4,5,46].

Early identif ication of severe and critical cases

High-risk children

Patients who have underlying diseases,such as congenital heart disease,chronic lung disease,nervous system disease,severe malnutrition,tumor,obesity,diabetes,genetic diseases,congenital and acquired immunodef iciency or immunocompetent are high-risk children for severe and critical cases.In addition,the disease progression of premature infants and low birth weight infants should be closely monitored [5,47-57].

Warning indicators

If any of the following criteria are met,it indicates the deteriorated conditions for the children.

Clinical characteristics(1) Persistent high fever for 3-5 days,a disease course longer than 1 week,and no improvements in symptoms or signs or progressive exacerbation.(2) Shortness of breath,ruling out the eff ects of fever and crying.(3)SpO2 ≤ 95% under the resting state.(4) Consciousness disturbances after convulsions,poor mental response,etc.(5)A prolonged capillary ref ill time on peripheral capillaries.(6) Severe gastrointestinal symptoms: vomiting,diarrhea,abdominal pain,etc.[4,5].

Blood biochemical indexes(1) Peripheral blood lymphocytes and/or thrombocytopenia signif icantly decreased,CRP and PCT signif icantly increased;(2) Progressively increased biochemical indexes,such as myocardial enzyme,liver enzyme,lactate dehydrogenase,brain natriuretic peptide,and lactic acid,etc.(3) Signif icantly increased D-dimer,IL-6,IL-10,and ferritin levels,and (4) Unexplained metabolic acidosis [4,5].

With severe underlying diseases or co-infected with other viruses and/or bacteria.

Diff erential diagnosis

Diff erential diagnosis should be mainly made to distinguish from respiratory tract infections caused by inf luenza virus,respiratory syncytial virus,rhinovirus,parainf luenza virus,adenovirus,human metapneumovirus and other coronaviruses,as well as from mycoplasma pneumoniae pneumonia,bacterial pneumonia,chlamydia pneumonia and Kawasaki disease.

It is necessary to pay close attention to mixed infection with other pathogens,including inf luenza virus,respiratory syncytial virus,Streptococcus pneumoniae,Staphylococcus aureus,and group AStreptococcus,when SARS-CoV-2 infection is diagnosed [4,5].

Treatment

Treatment principle

(1) Asymptomatic infection: no drug treatment is needed,but the changes of the disease should be closely monitored.(2) Mild cases: local application of IFN-α spray and symptomatic treatment.(3) Moderate cases: IFN-α nebulization therapy can be given,supportive and symptomatic treatment can be given according to the needs of the disease,with prone position ventilation under monitoring.(4) Severe cases: according to the needs of the disease,oxygen therapy,respiratory and circulatory support,glucocorticoid and blood purif ication should be considered.(5) Critical cases: on the basis of comprehensive treatment,the following treatment can be considered: active multi-disciplinary cooperation,early anti-inf lammation,multiple organ function support,correction of shock and coagulation dysfunction,prevention and treatment of complications,and antimicrobial therapy if necessary.In addition,for premature infants and small infants,nutrition,feeding,nursing,growth and development monitoring should be strengthened [4,5].

General treatment and monitoring

It is necessary to pay attention to the rest of the children and ensure that the children have suffi cient Calories and liquid intake to maintain water and electrolyte,internal environment stability and microecological balance.Taking probiotics such as clostridium butyricum or bif idobacterium to adjust intestinal f lora and improve immunity;to keep the respiratory tract unobstructed,wet the airway,and inhale oxygen if necessary.To closely monitor the vital signs,blood oxygen saturation,CRP,biochemical indexes related to liver,kidney and myocardial enzymology,blood coagulation function,arterial blood gas analysis,etc.according to the needs of the disease,and carry out chest imaging,inf lammatory factors,ferritin,etc.,if necessary [4,5,35,58].

Symptomatic treatment

The patient’s high fever should be actively controlled.Those with body temperature above 38.5 ℃ and obvious discomfort should be treated with antipyretic drugs in time.Common antipyretic drugs include ibuprofen and acetaminophen.It is necessary to keep the child quiet and control the convulsion in time when the child has convulsions.

Patients with increased and sticky respiratory tract secretions should be administered aerosol expectorant therapy.The recommended drugs for atomization inhalation include acetylcysteine solution or ambroxol hydrochloride solution for inhalation.Suction sputum after nebulization if necessary.

Patients with diarrhea should be comprehensively evaluated for water-electrolyte imbalance and dehydration.Oral rehydration salts are preferred for patients with mild dehydration,and intravenous rehydration is required for severe cases.Pulmonary conditions should be closely monitored during intravenous rehydration.Intestinal probiotics such as Clostridium caseinate (diphosphate) live bacteria powder and other intestinal microecological preparations can be taken to relieve diarrhea symptoms and shorten the course of the disease.Montmorillonite powder/suspension could be added as appropriate if necessary.

Patients with acute laryngitis or acute laryngotracheitis should be evaluated the degree of upper airway obstruction and hypoxia as soon as possible.To keep the air moist and give oxygen therapy timely,meanwhile,to avoid irritability and crying,ensure adequate f luid intake,and maintain water-electrolyte balance in children.Glucocorticoids are preferred for medical treatment.Mild cases can be treated with a single dose of dexamethasone orally 0.15-0.60 mg/kg,with a maximum dose of 16 mg;or oral prednisolone 1-2 mg/(kg·d),with a maximum dose of 60 mg/d.Moderate and severe cases should be treated with oral dexamethasone (0.6 mg/kg,with a maximum dose of 16 mg).For patients cannot be orally administered,intravenous or intramuscular injections were recommended.Glucocorticoid atomization inhalation can also be given at the same time,and the common drugs include Budesonide and Fluticasone Propionate.In emergency cases,atomization inhalation of L-epinephrine can also be used to rapidly relieve upper airway obstruction symptoms,0.5 mL/kg(maximum 5 mL) each time,lasting for 15 min.If the symptoms can’t be relieved,repeated inhalation could be performed 15-20 min later.For severe cases of airway obstruction,endotracheal intubation or tracheotomy,mechanical ventilation should be performed to maintain airway patency.

If patients have wheezing and lung wheezing,atomization inhalation of bronchodilators and glucocorticoids can be added on the basis of comprehensive treatment.Common drugs include albuterol,ipratropium bromide,budesonide,and f luticasone propionate.

Patients with a rash should exclude drug eff ects and aggravation of pre-existing skin diseases.Mild cases can be treated with oral antihistamines,and severe cases require systemic glucocorticoid or IL-6 inhibitors.Attention should be paid to skin barrier repair and symptomatic treatment in local skin lesions,and glucocorticoid preparations should be externally applied to the skin lesions if necessary.Suspected or conf irmed MIS-C should be treated according to the principles of MIS-C treatment [4,5,35,59-61].

Antiviral therapy

There are no specif ic antiviral drugs approved for pediatric patients with SARS-CoV-2 infection in China.

IFN

According to domestic and international studies related to the use of IFN-α in the treatment of viral infectious diseases including SARS-CoV-2 infection,IFN-α can reduce viral load,and early use can help to reduce symptoms and shorten the disease course.IFN-α can be used for the treatment of SARS-CoV-2 infection in children [62-66].

The recommended usage is as follows: (1) IFN-α spray:1-2 sprays on each side of the nasal cavity,8-10 sprays to the oropharynx for 8-10 times/day,with a treatment course of 5-7 days.IFN-α sprays can be used in children with asymptomatic infections and upper respiratory tract infections.(2) IFN-α nebulization: IFN-α 200,000-400,000 IU/kg or 2-4 μg/kg in 2 mL normal saline,nebulization 2 times per day for 5-7 days.IFN-α nebulization can be used in children with lower respiratory tract infections such as pneumonia.

Small molecule antiviral agents

Currently,emergency conditionally approved small molecule antiviral agents available for the treatment of COVID-19 include: the co-packaged combination of Nirmatrelvir and Ritonavir Tablets (Paxlovid),Molnupiravir Capsules and Azvudine Tablets.The applicable population is adult patients with mild to moderate disease within 5 days of onset and with high-risk factors for progression to severe disease.The co-packaged combination of Nirmatrelvir and Ritonavir Tablets (Paxlovid) has been approved to be used in 12-17-year-old patients (weight greater than 40 kg)within 5 days of onset who are mild,medium and have high-risk factors advancing to severe disease in the United States,Japan and other countries.The recommended usage:Nelmatavir 300 mg was administered concomitantly with Ritonavir 100 mg per 12 h for 5 days.Read the instructions carefully before use.The applicable population,indications,and other small molecule antiviral agents approved for the treatment of COVID-19 are adjusted according to the offi cial NMPA release [4,5,35].

Monoclonal antibodies

The Amubarvimab/Romlusevimab (BRII-196/BRII-198)combination is applied for the treatment of adults and adolescents (12-17 years of age,body mass ≥ 40 kg) with mild/moderate disease and with high-risk factors for progression to severe disease.The applicable population and indications are adjusted according to the offi cial NMPA release.The doses of the two drugs were 1000 mg,respectively,and the two drugs were diluted with 100 mL of normal saline before administration and administered by intravenous sequential infusion.The intravenous drip rate shall not exceed 4 mL/min,and flush the tube with 100 mL normal saline in between.Patients need to be monitored clinically during the infusion and observed for at least 1 h after the completion of the infusion [4,67].

COVID-19 immunoglobulin

Immunoglobulin is restricted to patients with high-risk factors,high viral load and rapid disease progression in the early course of the disease.The dose is 100-400 mg/kg by intravenous infusion,and it can be reinfused the next day according to the patient’s condition,for a total of no more than 5 times [4,5,35].

Convalescent plasma therapy

Convalescent plasma therapy is only used early in the course of the disease in children with high-risk factors,high viral load,and rapid disease progression.The infusion dose is 200-500 mL (4-5 mL/kg),and the decision to reinfuse can be determined according to the patient condition and the viral load [4,5].

Antibacterial drugs

Rational use of antibacterial drugs,especially to avoid the combination of broad-spectrum antibacterial drugs.It is recommended to empirically select antibacterial drugs as early as possible for those patient with high suspicion of secondary bacterial infection.The selection of antibiotics is mainly based on the distribution characteristics of the local pathogen spectrum of bacterial infection,or according to the results of bacterial culture and drug sensitivity [4,5,35].

Treatment of severe and critical cases

On the basis of symptomatic treatment,it is recommended to actively prevent and treat complications,underlying diseases,secondary infection,and timely perform organ function support.

Respiratory support

Children who undergo non-invasive mechanical ventilation for two hours without improvements in conditions,or cannot tolerate non-invasive ventilation,with increased airway secretions,severe cough,or hemodynamic instability,should be subjected to invasive mechanical ventilation promptly.The invasive mechanical ventilation should adopt low tidal volume “lung protective ventilation strategy” to reduce ventilator related lung injury.Prone position ventilation is recognized as an eff ective respiratory support measure,and prone position ventilation should be given as much as possible for at least 12 h per day whether it is nasal catheter oxygen inhalation,nasal high-f low,non-invasive respiratory support,or invasive respiratory support.If necessary,lung recruitment,or extracorporeal membrane oxygenation(ECMO) can be applied [4,5,35,68].

Circulation support

On the basis of full f luid resuscitation in critical children with shock,microcirculation should be improved,vasoactive drugs should be used rationally,and hemodynamic monitoring should be performed if necessary [4,5,35,68].

Glucocorticoids

The indications for the use of glucocorticoids should be strictly controlled.For severe and critical cases with progressive deterioration of oxygenation index,rapid imaging progress and excessive activation of inf lammatory reaction,glucocorticoids can be used for a short period of time (3-5 days).Methylprednisolone 1-2 mg/kg/day,intravenous injection,or dexamethasone 0.2-0.4 mg/kg/day (maximum dose not exceeding 6 mg),intravenous injection,once a day.Long-term and high-dose use of glucocorticoids should be avoided to minimize adverse eff ects [4,5,35,68-70].

Anticoagulation therapy

It is necessary to evaluate the risk factors of venous thrombosis in patients,give preventive anticoagulant therapy for those with the risk factors,and monitor coagulation function at the same time.Anticoagulation therapy can be used for children with signif icantly increased D-dimer or high risk of thrombosis,and low molecular weight heparin calcium is preferred[4,5,35,68].

IL-6 antagonists

Topirazumab can be used in severe and critical patients with signif icantly increased IL-6 levels in laboratory tests.Usage:The f irst dose is 4-8 mg/kg,the accumulated maximum dose is 400 mg,diluted to 100 mL with normal saline,and infused over ＞ 1 h.For the patients with poor effi cacy after the f irst dose,an additional application can be performed once after 12 h of the f irst dose (the dose is the same as before).The cumulative frequency is up to 2 times,and the maximum single dose not exceed 800 mg.Attention should be paid to the occurrence of allergic reactions,and topirazumab is contraindicated in children with active infections such as tuberculosis[4,5,35,68].

Bronchoscopic interventional therapy

When severe and critical cases have obvious airway obstruction,interventional therapy such as bronchoscopy,bronchoalveolar lavage and forceps can be performed under three-level protective measures [71].

Blood purif ication therapy

The blood purif ication system includes plasma exchange,adsorption,perfusion,blood/plasma f iltration,etc.It is recommended to be used only when there are indications such as acute renal injury and severe metabolic acidosis,or for the treatment of severe and critical patients in the early and middle stages of cytokine storm [4,5,35,68,72].

Key points for treatment of serious complications

COVID-19-related encephalopathy and ANE

Such patients should actively control their body temperature,give mannitol and other treatments to reduce intracranial pressure,sedation and anticonvulsant;mechanical ventilation through tracheal intubation shall be carried out in case of rapid progress;high dose of methylprednisolone 20-30 mg/(kg·d) (the maximum dose is not more than 1000 mg/d) should be given as early as possible for 3 days,and then the dose should be gradually reduced according to the condition;IVIG can be injected intravenously and administered in 1-2 days with a total amount of 2 g/kg.For those with inf lammatory factor storm prompted by signif icant increase of IL-6 or other laboratory parameters,blood purif ication and Tozumab should be selected as appropriate.Cocktail therapy (vitamin B1,vitamin B6,levocarnitine,etc.) can be used to improve mitochondrial metabolism when metabolic encephalopathy cannot be excluded.As for COVID-19-related encephalitis,meningitis,Guillain-Barre syndrome and other related diseases,the treatment principles are the same as those caused by other causes [4,35,45,46].

Fulminant myocarditis

Patients with fulminant myocarditis should be closely monitored and evaluated for hemodynamic status,maintain hemodynamic stability and organ function,actively nourish and protect myocardium,and add immunosuppressive therapy.Methylprednisolone and IVIG can be given at doses of 1-2 mg/ (kg·d) and 2 g/kg,respectively.In case of acute heart failure,positive inotropic drugs,diuretics and vasodilators can be used.Atropine or isoproterenol can be used when bradycardia or complete atrioventricular block occurs.For patients with ventricular tachycardia or ventricular f ibrillation,electric shock cardioversion is preferred,and amiodarone can be used for cardioversion.If necessary,temporary cardiac pacemaker can be installed or ECMO treatment can be performed [22,73].

MIS-C

The principle of treatment is to prevent inf lammation,correct shock and support organ function as soon as possible on the basis of symptomatic supportive treatment.For cases who meet the diagnostic criteria of MIS-C,IVIG and methylprednisolone at the doses of 2 g/kg and 1-2 mg/(kg·d)are the f irst choice for treatment;if there is no improvement or aggravation,methylprednisolone is given at a large dose of 20-30 mg/(kg·d),or immunotherapy includes TNF-α blocker (inf liximab) is recommended.For patients who meet the criteria of both MIS-C and Kawasaki disease,glucocorticoids can be used according to the standard therapy of Kawasaki disease.For patients with signif icantly elevated platelet count,it is recommended to add low-dose aspirin[3-5 mg/(kgd),maximum dose ≤ 81 mg/d] as appropriate until platelet count and coronary artery return to normal.But for cases with active bleeding or with serious bleeding risk or with platelet count ≤ 80 × 10 9/L aspirin should be avoided to reduce the risk of aggravating bleeding [4,5,23,74-76].

Acute renal injury

Critical cases can be complicated with acute renal injury,thus we should actively look for the causes,such as hypoperfusion and drugs.Attention should be paid to maintaining the balance of water,electrolyte,and acid-base,while actively treating the cause of the disease.Continuous renal replacement therapy (CRRT) can be selected.The indications include: (1) hyperkalemia;(2) Severe acidosis;(3) Pulmonary edema or excessive water load due to ineff ective diuretics [77,78].

Psychotherapy

If children (especially older children) have emotional instability,tension and fear,anxiety and depression or other psychological disorders,they need to take active psychological intervention and psychological behavior treatment.Treatment methods mainly include psychological crisis intervention,cognitive behavior therapy,hypnotherapy,and the use of anti-anxiety or antidepressant drugs can be considered when necessary [4,5].

TCM treatment

The characteristics of TCM syndrome and core pathogenesis of SARS-CoV-2 infection in children are basically the same as that in adults.TCM can be used according to the 10th edition of the diagnosis and treatment protocol for COVID-19 jointly issued by the National Health Commission and the National Administration of Traditional Chinese Medicine,combined with the clinical symptoms and physiological characteristics of children patients [4,5].

The discharge criteria

When general conditions of patients improved apparently,with stable vital signs,normal body temperature lasting for more than 24 h,and the acute exudative lesions were shown to have improved signif icantly in chest imaging examinations,the patients could be changed to oral drug therapy.And,if no complications or no other conditions requiring further treatment occurred,the discharge could be considered [4,5,79].

Prevention

Specif ic prevention

Vaccination is still an effective way to prevent viral infection and reduce the rate of severe disease and the mortality of infection [80-84].Depending on different targets and techniques,several types of SARS-CoV-2 vaccines which include inactivated vaccines,nucleic acid vaccines,viral vector vaccines and protein subunit vaccines are currently marketed,with relatively higher safety of inactivated vaccines and protein subunit vaccines.However,for the Omicron variant,the protective effect of SARSCoV-2 vaccines proven to be effective against SARSCoV-2 infection to date requires further verification.The adverse reactions of SARS-CoV-2 vaccines were mainly pain and redness at the injection site,fatigue,fever,etc.

Children aged 3 years and older have been widely vaccinated with inactivated SARS-CoV-2 vaccines in China.While SARS-CoV-2 vaccines are not recommended for children within 6 months after confirmed SARS-CoV-2 infection,booster vaccinations may be considered after 6 months of infection and not limited to the same vaccine product.It is not currently recommended that SARSCoV-2 vaccines are administered simultaneously with other vaccines.The inoculation interval between SARSCoV-2 vaccines with others should be ＞ 14 days.Patients can be vaccinated urgently with rabies vaccine,tetanus vaccine and immunoglobulin without regard to this interval when it is required due to injuries caused by animals,trauma,etc.

Non-pharmaceutical interventions (NPIs)

The NPIs against respiratory virus infection predominantly refers to infection control measures such as personal protective measures,environmental disinfection and social policies,which can slow down the spread of virus,reduce the rate of virus infection,delay the peak of infection,limit the scope of infection and control the epidemic of disease.Present clinical research and practice have proven that NPIs,which can provide eff ective protection for children,has been emerged as the signif icant means of preventing SARS-CoV-2 infection in children.NPIs applicable to children include (1)Children over 2 years old wear medical surgical masks,and high-risk children can choose medical protective masks;(2)Correctly implement hand hygiene and recommend children to wash their hands with soap and f lowing water;(3) Keep social distance and isolate if necessary;(4) The room shall be well ventilated,and relevant articles shall be cleaned and disinfected.

Boosting immunity,protecting susceptible groups

A balanced diet,adequate sleep,keeping oral health,moderate exercise,regular schedule,avoiding excessive fatigue,and boosting immunity among children are powerful measures to preventing infection.Children also should maintain emotional stability and mental health actively.Moreover,if a mother is diagnosed or suspected to be infected with SARSCoV-2,the newborn and the mother should be separated timely,and specialists need to complete the newborn assessments,at the same time,ensure breastfeeding if possible.

Author contributionsAll authors contributed equally to this paper.

FundingNational Natural Science Foundation of China (72174138);High-level Public health Talents Training Program of Beijing Municipal Health Commission (2022-2-002).

Data availabilityData will be made available on reasonable request.

Declarations

Conflict of interestThe authors have no f inancial or non-f inancial conf lict of interest relevant to this paper to disclose.

Ethical approvalNot required.