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   Table of Contents      
REVIEW ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 1-10

COVID-19 in Children: A Review on Our Understanding So Far


1 Department of Ophthalmology, University College of Medical Sciences and Associated GTB Hospital, University of Delhi, New Delhi, India
2 Department of Neonatology, Lady Hardinge Medical College and Associated SSK Hospital and Kalawati Saran Children Hospital, University of Delhi, New Delhi, India

Date of Submission22-Apr-2021
Date of Decision16-Dec-2021
Date of Acceptance02-Jan-2022
Date of Web Publication28-Jan-2022

Correspondence Address:
Siddharth Madan
Department of Ophthalmology, University College of Medical Sciences and Associated GTB Hospital, University of Delhi, New Delhi 110095
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mamcjms.mamcjms_40_21

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  Abstract 


Clinical manifestations of SARS-CoV-2 in children are not typical. These range from relatively mild to no symptoms in 90% of patients to a severe Kawasaki like disease compared to adults. The outcome is usually favorable in children. There are relatively few studies related to coronavirus disease (COVID-19) in children, no major clinical trials exist. The experience of this novel disease in adults is being extrapolated to manage pediatric COVID-19 cases. This review summarizes the current understanding of pediatric COVID-19 with regards to the epidemiology, clinical manifestations and management.

Keywords: Childhood COVID-19, coronavirus disease, COVID-19, Kawasaki disease, SARS-CoV-2


How to cite this article:
Madan S, Srishti. COVID-19 in Children: A Review on Our Understanding So Far. MAMC J Med Sci 2022;8:1-10

How to cite this URL:
Madan S, Srishti. COVID-19 in Children: A Review on Our Understanding So Far. MAMC J Med Sci [serial online] 2022 [cited 2022 Aug 19];8:1-10. Available from: https://www.mamcjms.in/text.asp?2022/8/1/1/336734




  Introduction Top


Coronavirus disease 2019 (COVID-19) is caused by a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is a disease of great global public health concern. Children account for about 1% to 2% of total cases, and 6% of these are with severe manifestations requiring intensive care unit management. Infection with the novel coronavirus causing COVID-19 is observed after an incubation period of approximately 5.2 days.[1],[2],[3] The first pediatric case of COVID-19 confirmed by testing was reported in Shenzhen on January 20, 2020. Despite existing anecdotal case reports and series on pediatric COVID-19, the epidemiologic and clinical pattern of the COVID-19 in pediatric patients still remains unexplored and unclear.[4],[5]


  Epidemiology Top


Europe became one of the major clusters of the pandemic. The experience of the authors from France suggests that infants younger than 3 months with isolated fever should be tested for infection with novel coronavirus. Observation for 2 weeks after the onset of infection is crucial.[6] The primary established route of transmission is through infected aerosols and through respiratory droplets.[7] However, the role of children in transmitting this virus remains uncertain.[8] Most of the children who have been infected by this novel virus reported till now have a documented household contact and are usually showing symptoms before the adults giving a pointer that the possibility of children being an important reservoir for novel CoVs seems unlikely. Children are more likely to be asymptomatic virus shedders especially prolonged shedding in nasal secretions and stool has been observed in children without symptoms and the screening may yield falsely negative results. Adequate personal protective equipment use is warranted for all healthcare workers involved in pediatric care.[9] Adult patients infected with SARS-CoV-2 commonly present with fever, dry cough, dyspnea, myalgia, fatigue, or acute respiratory distress syndrome (ARDS) in older men with accompanying comorbidities.[10] When compared with adults, the number of pediatric patients who have been reported in literature is limited.[11],[12] Zheng et al. reported that a majority of the children had a similar pattern of symptoms [upper respiratory tract infection (URTI) and mild pneumonia] with a milder severity when compared with adults.[13],[14] Ma et al. in their single center descriptive study observed fever in 64% children versus 41.5% in adults; cough, 44% versus 48.5%; diarrhea, 6% versus 8.8%; and fatigue, 4% versus 7.6%.[15] Gastrointestinal symptoms, including abdominal discomfort, nausea, vomiting, abdominal pain, and diarrhea, are known in children infected with SARS-CoV-2.[16],[17] Although there is a phylogenetic homogeneity between SARS-CoV-2 and SARS-CoV, yet COVID-19 is observed to cause septic shock, ARDS, acute kidney injury, rhabdomyolysis, and disseminated intravascular coagulation. These features differentiate COVID-19 from SARS-CoV, Middle East respiratory syndrome (MERS-CoV), and seasonal influenza infections. They have not been commonly observed in children.

Zheng et al. concluded that children aged less than 3 years have shown more predispositions to infection with SARS-CoV-2 possibly due to a special respiratory tract structure infection, or an immature immune system. In addition, the compliance to wear adequate face mask is a limiting factor. Further, the clinical manifestations of COVID-19 in children are relatively mild possibly due to a more active innate immune response and healthier respiratory tracts with relatively less number of underlying disorders. Children are apparently more protected by their parents therefore the epidemiologic pattern of the disease varies. Alternatively, differences in receptors in the renin–angiotensin system and altered inflammatory responses to the infectious agent may account for variability in the clinical profile.


  Clinical Features/Risk Factors Top


Reports in 171 children out of a total of 1391 children at Wuhan Children’s Hospital concluded that the median age of the infected children was 6.7 years. About 41.5% of these children showed documented fever at any time during the illness. Other common signs and symptoms included cough and pharyngeal erythema as observed in previous reports. However, 15.8% of these children did not demonstrate any symptoms of infection or radiologic features of pneumonia and a few (12 children) who had radiologic findings pointing to pneumonia did not manifest clinically. Lymphopenia was reported in six patients (3.5%).[18],[19] The Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) study comprised a cohort of 100 Italian children who were less than 18 years of age included from 17 emergency departments, confirmed of COVID-19 using reverse-transcriptase polymerase chain reaction (RT-PCR) testing of the specimen from the standard nasal or nasopharyngeal swab. Children who were exposed to SARS-CoV-2 from an unknown source or from a source outside their family were contributors to 55% of total cases infected with SARS-CoV-2. Overall the clinical profile of these children remained same as observed in children in other parts of the world yet only a few patients had moderate to severe disease. Majority of the children underwent a chest radiograph rather than a computed tomography (CT) chest and therefore the total number of children manifesting pneumonia might have been under-reported.[20] Children with an underlying serious illness and younger than 1 year are at a higher risk for severe disease. About 23% of 345 laboratory confirmed children with COVID-19 from the United States had a known underlying condition. Chronic pulmonary disease (including asthma), cardiovascular, liver, neurologic, neurodevelopmental and dialysis requiring chronic kidney disease, immunosuppression, blood and endocrine disorders, and pregnancy have all been recognized as an underlying condition that accounted for a bad course of the disease. The extent of lymphopenia in children is not of severe proportions when compared with adults and so is the elevation in C-reactive protein (CRP).[21] Children have, however, demonstrated thrombocytopenia. The mechanism for these observations is unknown and could be the reason behind variability in clinical manifestations in children.[15] There seems to be a low prevalence of demonstration of positive blood culture results or sputum culture results in children presenting with pneumonia due to COVID-19.[22],[23]

Overall, the percentage of children infected with COVID-19 is less and also the number of children tested is apparently less; therefore, the actual numbers seem low. Also, children become rapidly negative for the test, if performed and so the burden of disease in children based on the test results seems uncertain.

The neurologic manifestations of COVID-19 which are reported in children include anecdotal reports of paroxysmal events (including seizures) involving a newborn and also an adolescent who developed status epilepticus.[24],[25],[26] The role of COVID-19 in the mentioned cases was uncertain as neither of the cases demonstrated SARS-CoV-2 in cerebrospinal fluid (CSF) and also other respiratory pathogens like rhinovirus/enterovirus were also detected in these cases. Axial hypotonia with drowsiness and moaning sounds in infants under 3 months who presented with fever and mild respiratory symptoms is also reported. However, the outcome was favorable in all with complete amelioration of signs without any antiviral or immunomodulatory therapy.[27] Neurologic manifestations in the form of headache, dizziness, encephalopathy, myositis, dysgeusia, and anosmia may be observed in adolescents. The association of majority of manifestations is due to COVID-19 in adults excepting loss of taste and smell. These findings are rarely reported in children. Children with neurologic disorders may need administration of immunosuppressive therapy in the form of steroids; therefore, there is a need to direct resources toward the children with special needs.


  Radiologic Manifestations Top


The CT manifestations of COVID-19 are generally less severe but similar when compared with adults.[28],[29],[30],[31],[32],[33],[34],[35],[36],[37] Chest radiograph may show evidence of pneumonia.[21] The common patterns on CT scan are the presence of ground-glass opacities followed by local bilateral shadowing unlike adults where bilateral patchy shadowing patterns are commonly observed.[38],[39] The role of CT scan in managing pneumonias due to COVID-19 in children remains a matter of debate. Also early treatment initiation with antivirals and supportive therapy is of value in children who may deteriorate faster. Performing a CT scan at presentation may not be of much relevance to children. Having said this, Ma et al. in their study indicated that lesions were subpleural in location in 95% of children followed by predisposition to the lower lung (65%), especially in the posterior segment (78%). The relative predisposition of the lower lobes lies in the fact that it is densely populated with bronchioles, blood vessels, and alveoli.[15] Also detecting a finding on a CT scan may not be a pointer to infection with COVID-19 considering other causes of viral pneumonias in children. CT scan offer no added advantage in monitoring recovery in children with community acquired pneumonia due to SARS-CoV-2. Clinical examination always prevails over investigations of any kind. The harmful effects of low-dose ionizing radiations in precipitating a cancer in children have to be recognized as researched by Hong et al.[40]


  Pregnancy and COVID-19 Top


As COVID-19 may increase the risk for complications in pregnancy, a close maternal and fetal monitoring is of importance. Management principles include early isolation, aggressive infection control procedures, fetal monitoring, limiting fluid overload, laboratory diagnosis of infection with early initiation of antibiotic administration for a possible risk of secondary bacterial infection, and prompt oxygen therapy with early mechanical ventilation for progressively worsening respiratory failure. Considering empiric treatment for influenza may be wise in antenatal females who are waiting for a diagnostic testing for COVID-19.[41] A possibility of in utero transmission has been suggested and the youngest newborn to have been infected with SARS-CoV-2 was 30 hours old. However, data from the case series by Chen et al. and Zhu et al. in 18 women (19 infants) who were infected in the third trimester of pregnancy with SARS-CoV-2 has pointed to no laboratory evidence of vertical transmission.[42],[43] Samples from the amniotic fluid, cord blood, and throat swab in the neonates tested negative for SARS-CoV-2.[42] The infants who demonstrated symptoms of shortness of breath and cyanosis also tested negative ruling out a possible intrauterine transmission. Therefore, as we stand today, it is difficult to say whether SARS-CoV-2 can be transmitted from mother to fetus. This also supports the proposition that the newborn born to a mother with COVID-19 should preferably be isolated to avoid transmission to other neonates in the nursery or intensive care setting. Transmission of the novel coronavirus through breast milk is not known as of now. Anecdotal case reports exist where the SARS-CoV-2 antibodies have been observed in the breast milk; however, till further research supports this fact, lactating females suffering from COVID-19 can safely feed their newborns once they are considered noninfectious after a multidisciplinary evaluation.[44] Experience from SARS, MERS, and other respiratory infections suggests that a severe clinical course may follow in pregnant patients infected with SARS-CoV-2.


  Multisystem Inflammatory Syndrome in Children Top


A webinar on Pediatric Intensive Care-COVID-19 International Collaborative on May 2, 2020 concluded that COVID-19 infection leading to critical illness in children remains very infrequent as on date.[45] A small number of children have been reported to develop a more serious inflammatory syndrome in temporal association with COVID-19 in the community, often requiring hospitalization, and occasionally necessitating intensive care as observed first in Europe and recently in cities along the East Coast of the United States, with anecdotal reports in the Midwest and South. Children infected with SARS-CoV-2-associated pediatric multisystem inflammatory syndrome present with persistent fever, inflammation, evidence of poor function in a single organ or many organs, and other specific clinical and laboratory features, in the absence of other known infections. Some of these children have part or all of the features observed in Kawasaki disease and demonstrate clinical and laboratory signs of cytokine storm syndrome.[45] However, the PCR test and antibody test for SARS-CoV-2 may be positive or negative. This multisystem inflammatory reaction due to a massive cytokine release may be attributed to significantly high blood levels of interleukin (IL)-1-β, IL-1-RA, IL-7-10, basic fibroblast growth factor 2, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, IP10, monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP)1α, MIP1β, tumor necrosis factor alpha, interferon (IFN) gamma, platelet-derived growth factor B, and vascular endothelial growth factor A that have been reported.[4],[46],[47],[48],[49],[50]


  Diagnostic Criteria Top


The diagnostic criteria [World Health Organization (WHO)][51] were as follows: children and adolescents 0 to 18 years of age with fever ≥3 days and any two of the following:
  1. rash or bilateral nonpurulent conjunctivitis or mucocutaneous inflammation signs (oral, hands, or feet),
  2. hypotension or shock,
  3. features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities [including echocardiogram (ECHO) findings or elevated Troponin/NT-proBNP],
  4. evidence of coagulopathy [prothrombin time (PT), partial thromboplastin time (PTT), elevated D-dimer],
  5. acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain),
  6. elevated markers of inflammation such as ESR, CRP, or procalcitonin,
  7. no other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, and
  8. evidence of recent COVID-19 infection (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19.


Treatment: The child requires appropriate supportive care preferably in the intensive care unit for the management of cardiac dysfunction, shock, coronary involvement, and multiorgan dysfunction. Drugs that need to be used include intravenous immunoglobulin (IVIG) in a dose of 2 g/kg over 12 to 24 hours, methylprednisolone 1 to 2 mg/kg/day, and empirical administration of broad-spectrum antimicrobials. If no improvement is noted with the above-mentioned therapies or any deterioration is noted, repeat administration of IVIG and high-dose corticosteroid (methylprednisolone 10–30 mg/kg/day for 3–5 days) are required which need to be tapered over 2 to 3 weeks while monitoring inflammatory markers. Other drugs include aspirin: 3 mg/kg/day to 5 mg/kg/day up to a maximum dose of 81 mg/day (if thrombosis or coronary aneurysm score is >2.5), low molecular weight heparin (enoxaparin): 1 mg/kg twice daily subcutaneously (if patient has thrombosis or giant aneurysm with absolute coronary diameter ≥8 mm or ≥10 Z score (coronary aneurysm score ≥10) or left ventricular ejection fraction <30% or D-dimer ≥5 ULN); clotting factor Xa should be between 0.5 and 1 IU/mL. The use of biologicals is indicated only after expert consultation and should be used at tertiary care only. For children with cardiac involvement, repeat electrocardiogram 48 hourly and repeat ECHO at 7 to 14 days and between 4 and 6 weeks (and after 1 year if initial ECHO was abnormal) is recommended.


  Neonatal COVID-19 Top


It remains unclear whether SARS-CoV-2 can be vertically transmitted from mother to her fetus. Pathologic findings consistent with maternal vascular malperfusion include decidual arteriopathy, fibrinoid necrosis, and amniotic membrane arteriole hypertrophy.[52] Literature gives a pointer that SARS-CoV-2 infection can cause inflammatory and vascular changes of the placenta and these changes could have deleterious effects on both mother and fetus. Majority of infants born to mothers infected with SARS-CoV-2 or who are in the convalescent stage of the disease do not have viremia, congenital infection, or viral replication in the nasopharynx.[52] Appropriate ways to screen neonates have not yet been established and so are the immunoglobulin M cutoffs as neonates produce less immunoglobulins than adults. SARS-CoV-2 RNA is detected in both neonate and placenta along with elevated level of transaminases and neutropenia due to infection of the liver with the virus. The proinflammatory effect of SARS-CoV-2 causes changes in neonatal inflammation and immunity. Infection of the placenta can trigger a fetal inflammatory response, leading to multiorgan system damage and predisposition for negative developmental consequences.[53] Evidence is strong to suggest that maternal inflammation associated with SARS-CoV-2 may predispose to a long-term risk of neuropsychiatric disorders in children.[53] Death of the fetus and preterm delivery due to fetal distress have been reported in pregnant women. High levels of inflammatory markers in neonates born to mothers infected with SARS-CoV-2 gives a pointer to the activation of immune system in the mother–fetus.[54] Respiratory distress is also observed in neonates infected with SARS-CoV-2.[55]


  Diagnosis Top


Nucleic acid amplification test conducted on respiratory secretions is currently the gold standard for diagnosing COVID-19. The most common methodology used commercially is the RT-PCR test. The sensitivity of the test in diagnosing COVID-19 is higher in the early phase of the disease and reduces after the first week. The results of the test are often negative in children and adolescents with the Kawasaki disease like multisystem inflammatory syndrome. Moreover, the data are limited regarding the sensitivity of RT-PCR in children. False-negative results can be reported in 30% to 50% of the cases.


  Management and Prognosis Top


Treatment strategies for children are commonly deciphered from the experience in the adult patients infected with SARS-CoV-2. [Table 1] and [Table 2] depict the management guidelines in children under the age of 18 years suffering from COVID-19.[51] Home isolation or an isolation setting on an outpatient basis seems feasible for children with asymptomatic or a mild infection. Symptomatic and supportive care for clinical manifestations in the form of URTI or a gastrointestinal disturbance may be administered. Adequate hydration and maintenance of electrolyte balance are crucial. Health education of the family members for hygiene practices is important. As a part of conservative management, there is a belief that steam inhalation used as a home remedy for common colds and URTI helps loosen mucus, open nasal passages, and aids in reduction of mucosal inflammation and also possibly the heat inhibits replication of viruses. This practice resulted in increased number of burn cases with scalds presenting to 50% of centers in the United Kingdom where the prevalence of COVID-19 was higher.[56] Parental education is must in this regard as the existing evidence in weak pertaining to the role of heat in killing the virus. No approved specific therapy for COVID-19 exists in pediatric patients. Based on limited literature in children, no clear recommendations can be proposed. Sanders reported that most promising treatment for COVID-19 is with remdesivir; however, no proven effective management therapy is available.[57] Clinically significant evidence is lacking that shows the role of hydroxychloroquine (HCQS) or chloroquine in the treatment of COVID-19. No specific dosage recommendation for HCQS in children exists. However, a dose of 3 to 5 mg/kg/day (maximum dose 400 mg) hydroxychloroquine sulfate intravenous twice daily for 5 days with careful monitoring for QT interval (the time from the start of the Q wave to the end of the T wave in electrocardiogram) prolongation has been suggested in children. The drug may be used in pregnancy or during lactation with overweighing benefits over the risks.[58],[59],[60],[61] The Infectious Diseases Society of America (IDSA) guideline panel has recommended that concurrent usage of hydroxychloroquine and azithromycin can only be advised based on its study in clinical trial as the combined usage commonly prolongs corrected QT interval (QTc).[62] Each of these drug regimens was associated with increased frequency of ventricular arrhythmias and reduction in in-hospital survival in patients with COVID-19. INF-α2b nebulization in a dose of 100,000 to 200,000 IU/kg for mild cases and twice the dose in severe cases administered two times/day for 5 to 7 days has been used in pediatric cases.[7] Lopinavir ritonavir (protease inhibitors for HIV infection) combination seems to have negligible to no role in the treatment of COVID-19.[63] Remdesivir is a novel nucleotide analog that has demonstrated reasonable activity against SARS-CoV-2 in vitro. Its efficacy and dosage regimen in children are not well established.[64] Intravenous administration of 5 mg/kg/dose once daily to a maximum dose of 200 mg on day 1, followed by 2.5 mg/kg/dose once daily up to a maximum of 100 mg was used in a phase 3 Ebola study in children.[65] However, its duration of treatment in COVID-19 is still not known. Clinical trials for favipiravir are under process and there is no direct evidence to support its usefulness for pediatric patients. Though the agent is more potent than Lopinavir ritonavir yet its use in patients with COVID-19 is still uncertain.[66] WHO, Centers for Disease Control and Prevention (CDC), and IDSA guidelines suggest against the use of corticosteroids in COVID-19 cases without severe manifestations in the form of ARDS.[66] Tocilizumab is an IL-6 receptor inhibitor that has shown promising results in cytokine release syndrome. Isolated reports give a pointer to its effectiveness in managing COVID-19 cases but well-established clinical trials are lacking.[66] Convalescent plasma use has been reported to be safe and has shown benefit in reducing viral load enhancing clinical results in patients infected with SARS-CoV-2. High doses of IVIG have been proposed but lack strong evidence. Recently, plasma therapy is showing promising results but its establishment as a chief modality of care needs to be testified.[67] Children manifesting respiratory distress syndrome may require administration of high-dose pulmonary surfactant, inhalational nitric oxide with high-frequency oscillatory ventilation. Intravenous glucocorticoid administration with or without immunoglobulins and extracorporeal membrane oxygenation are options in severely sick babies.[68]
Table 1 Management guidelines for COVID-19 based on the severity of the disease

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Table 2 Management of a child with acute respiratory distress syndrome and shock

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No randomized clinical trial data is available currently to guide appropriate treatment of children presenting with life-threatening COVID-19 including severe pneumonia, ARDS, and septic shock. WHO has not recommended any specific treatment in children with severe manifestations of COVID-19. In the current scenario, although vaccine administration initiated for children between 15 to 18 years in India, the children under 15 years are still vulnerable to COVID-19 and await vaccine administration. The potential of this novel virus to mutate may be a hindrance to design the vaccine.[69] No causal relationship has been confirmed with substantial evidence that bacillus Calmette−Guérin (BCG) vaccination may be associated with reduced number of severe and/or fatal COVID-19 cases.[70],[71] Clinical studies have begun in countries to determine the protective role of BCG vaccination from SARS-CoV-2.

Social distancing protocols and outpatient department (OPD) etiquette may not be followed as desirable by children; therefore, the role of the parents is imperative.[72] Child over 2 years and an accompanying parent in any case must wear a mask mandatorily. Specific precaution needs to be taken when auscultating a neonate, performing retinopathy of prematurity screening in intensive care units and nursery and also while conducting ear, nose, and throat examination in children. A potential risk of tear and conjunctival transmission of SARS-CoV-2 exists.[73] Necessary history may be taken on phone and tele-consultation must be encouraged wherever feasible. Most of the clinical information may be gathered from the parents more so in preverbal children. Assessment of clinical photographs of the child might be of help in ophthalmic surgical cases.[72] Close play areas and soft toys should be removed from the clinics. Parents of children with special needs and those with low vision should be discouraged to bring these children to OPDs, as they are potentially at a greater risk of contracting the disease.

The HCQ should not be used for prophylaxis in children who are younger than 15 years of age and suffering from glucose-6-phosphate dehydrogenase deficiency as the drug may precipitate hemolysis. Children on immunosuppressive therapy must continue their medications and so should the dialysis in children with chronic kidney disease be continued with appropriate precautions. A separate room with a dedicated staff should be posted and dialysis in these cases may be performed last.[73] Treatment for COVID-19 in such cases is mostly supportive with necessary isolation protocols. However, early diagnosis of pneumonia and ARDS must be established and treated accordingly. Live-related donor transplants especially in renal cases may be postponed until the outbreak has abated.[74] As the pandemic of COVID-19 evolves, the guidelines, diagnostic, and management practices may change.

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Abstract
Introduction
Epidemiology
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Radiologic Manif...
Pregnancy and CO...
Multisystem Infl...
Diagnostic Criteria
Neonatal COVID-19
Diagnosis
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