COVID-19 associated pediatric complications

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Harmeet Kharoud M.D.[2]; Asra Firdous, M.B.B.S.[3] Neepa Shah, M.B.B.S.[4]; Abdelrahman Ibrahim Abushouk, MD[5]

Overview

Cases of COVID-19 have been reported in children, yet the prevalence is lower than adults. It ranges from asymptomatic, mild cases to Multisystem inflammatory syndrome in children MISC. As asymptomatic patients do not get tested for COVID-19 and are potential carriers for viral transmission, high clinical suspicion is required to prevent such transmissions to a population at risk of developing severe disease. A pediatrician should be cautious to exclude other causes of respiratory illnesses like seasonal influenza before any diagnostic tests. As no effective treatment has been approved by the FDA yet, the main goal of managing patients with COVID-19 is to treat the symptoms, provide supportive care, prevent and treat complications, and provide organ function support.

Historical Perspective

Classification

  • Asymptomatic presentation
    • Children present with no clinical signs or symptoms with normal chest imaging.
    • Among 2143 children with COVID-19 infection 4% of children were asymptomatic.
    • According to one study 14.2% of children were asymptomatic. Another study showed 18% of asymptomatic children with COVID-19.
  • Mild Disease
    • Children present with mild symptoms including fever, fatigue, myalgia, cough.
    • Among 2143 children with COVID-19 infection 51% of children had a mild disease of COVID-19.
    • A study showed 36.3% of children present with a mild form of the disease.
  • Moderate
    • Children present with pneumonia with symptoms or subclinical disease with abnormal chest imaging.[1]
    • Among 2143 children with COVID-19 infection 39% of children had a moderate presentation.[1]
  • Severe
    • Children present with dyspnea, central cyanosis, hypoxia.[1]
    • Among 2143 children with COVID-19 infection 5% of children had a severe presentation.[1]
    • 2.1% of children present with a severe form of COVID-19 disease.
    • Children with underlying comorbidities are more susceptible to getting severe COVID-19 disease.
  • Critical

Pathophysiology

Tropism

Activation of Host Immune Reponses

  • SARS-CoV2 is known to cause a delayed-type I interferon response during the initial phases of infection.
  • Infection and viral replication lead to an activation of neutrophils, macrophages, and monocytes. Th1/Th17 induced specific antibodies are produced.
  • RNA viruses such as SARS-CoV and MERS are recognized pathogen associated molecular patterns by endosomal RNA receptors, TLR3 and TLR7 and the cytosolic RNA sensor, RIG-I/MDA5.[21]
  • This leads to downstream activation of NF-KB signaling cascade and nuclear translocation of transcription factors, which in turn leads to the production of type 1 interferon pro-inflammatory cytokines.
  • Coronavirus Nucleocapsid Inhibits Type I Interferon Production by Interfering with TRIM25-Mediated RIG-I Ubiquitination.

Comorbidities

  • The 3 most common comorbidities in children [29].
    • Chronic Lung disease
    • Cardiovascular disorder
    • Immunocompromised children

Co-infections

Co-infection with other pathogens were reported in 27% of cases. Some common microorganisms associated with SARS-CoV-2 infection in children are:

Causes

Differentiating COVID-19 in Children from other Diseases

Epidemiology and Demographics

Incidence

Prevalence

Prevalence of coronavirus in children is less compared to adults as the number of cases are less and most of the cases are with the mild presentation.[36][37]

  • The following data is from CDC Surveillance from January 22 to May 30.[29]


ICU and total hospitalization in children

  • <9 years of age among 20,458 children[29]
  • 10-19 years of age among 49,245 children[29]
Data of children with hospitalized children and ICU admissions as reported by CDC for a period of January 22 to May 30[29]
Age All admissions in the hospital and ICU divided according to associated comorbidity
<9 years (20458 cases) All patients (20458) Among all patients with reported underlying disease (619) Among all patients with no reported underlying disease (2277)
All admissions in the hospital including ICU ICU admissions All admissions in the hospital including ICU ICU admissions All admissions in the hospital including ICU ICU admissions
848/20458 (4.1%) 141/20458 (0.7%) 138/619 (22.3%) 31/619 (5%) 84/2277(3.7%) 116/2277 (0.7%)
10-19 years (49245 cases) All patients (49245) Among all patients with reported

underlying disease (2076)

Among all patients with no reported underlying disease (5047)
All admissions in the hospital including ICU ICU admissions All admissions in the hospital including ICU (2076) ICU admissions All admissions in the hospital including ICU (5047) ICU admissions
1234/49245 (2.5%) 216/49245 (0.4%) 309/2076 (14.9%) 72/2076 (3.5%) 115/5047 (2.3%) 17/5047 (0.3%)

Age

  • According to the data published by CDC for a period of January 22 to May 30[38] [29]
    • The cumulative incidence of COVID-19 cases in children age 0-9 is 51.1 from 20,458 cases.
    • The cumulative incidence of COVID-19 cases in children age 10-19 is 117.3 from 49,245 cases.

Race

Non-Hispanic American Indian or Alaska Native persons have an age-adjusted hospitalization rate approximately 5 times that of non-Hispanic White persons, while non-Hispanic Black persons and Hispanic or Latino persons each have a rate approximately 4.5 times that of non-Hispanic White persons[39]

Gender

  • According to the data published by CDC for a period of January 22 to May 30[29]
    • The cumulative incidence of COVID-19 cases:
      • Boys age 0-9 years is 52.5 (1.7%) out of 10,743
      • Boys age 10-19 years is 113.4 (3.8%) out of 24,302
      • Girls age 0-9 years is 49.7 (1.4%) out of 9,715
      • Girls age 10-19 years is 121 (3.7%)out of 24,943

Region

Risk Factors

Breastfeeding

Vertical transmission

  • A study by Marzieh Zamaniyan et all [46] discusses about a pregnant women who developed severe pneumonia with 32 weeks of gestation delivered a healthy pre-term baby without COVID-19 symptoms.
    • The first neonatal nasal swab, vaginal secretion and umbilical cord RT-PCR was negative.
    • However, the second neonate and amniotic sample for RT-PCR tested positive for COVID-19. This study shows more research needs to be done to identify more cases with possible intrauterine infection.
  • Another study documented a possible vertical transmission as increased levels of neonatal Ig M antibodies were found in 3 cases.[47]
    • Seropositivity with IgM antibodies found in neonates needs reflex testing for example - virus neutralization, IgG avidity index, molecular and immunoblotting. A study by Dong E et all[48] discussed decreasing levels of neonatal IgM antibodies in the serum 2 weeks later. So far RT-PCR is the preferred test to docuement for possible vertical transmission.
  • Pregnant women with severe COVID-19 pneumonia were found to have placental inflammation which increases the risk for transplacental infection and pre-term births.[44]
  • Detection of IgM and IL-6 in neonates serum is used as one of the markers for possible transplacental transmission.
  • Some studies which detected the virus hours to days after birth in the nasopharyngeal samples and hence those newborns could have been exposed to the virus after birth via the nosocomial infection.

Screening

Natural History, Complications, and Prognosis

Complications

A. Multisystem Inflammatory Syndrome in Children (MIS-C)

B. Acute Heart Failure

C. Negative effects of lockdown in children

Diagnosis

Diagnostic Study of Choice

In case of clinical suspicion, the best diagnostic test to diagnose COVID-19 infection in children is Reverse-Transcriptase Polymerase Chain Reaction

History and Symptoms

  • Presentation of COVID-19 is less severe in children as compared to adults. Most of the children are asymptomatic.[53]
  • According to CDC, as of April 2, 2020, 1.7% confirmed cases of COVID-19 were reported in children aged <18 years age among the total number of confirmed cases of COVID-19.
  • Illness severity of COVID-19 in children ranges from asymptomatic to critical.
  • The incubation period of SARS-CoV-2 varies from 2 to 14 days with most patients developing symptoms 3 to 7 days after exposure.[53]

The common symptoms of COVID-19 infection in children are:

  • Fever and Cough are one of the most common symptoms reported in children. One study showed fever is prevalent in 47.5% of children and cough in 41.5% among the 1124 children with COVID-19.According to the CDC, fever, and cough was reported in 56% and 54% of children with COVID 19
  • Dyspnea, nasal congestion, pharyngeal erythema, and sore throat are also common presentations in children.
  • Gastrointestinal symptoms-The gastrointestinal manifestation in COVID-19 positive children are diarrhea, vomiting, abdominal pain, nausea, and anorexia. Children can present with gastrointestinal symptoms in the absence of respiratory symptoms.
  • Cutaneous Findings-The cutaneous findings in COVID-19 positive children range from petechiae to papulovesicular rashes to diffuse urticaria. These appear early in the course of COVID-19 and result secondary to viral replication or circulating cytokines. Many patients with COVID-19 are presenting with chilblains like lesions unrelated to cold. Chilblains are painful or itchy swellings of the toes and fingers, caused by small-vessel inflammation from repeated exposure to cold. A retrospective case series presented 22 children and adolescents with COVID-19 who presented with chillblains lesions. [54][55]
  • Neurological manifestation- The presentation of neurological manifestation in children is rare. However, a case report described a rare case of a 6-week old infant with COVID-19 who had 10-15 seconds episodes of upward gaze and bilateral leg stiffening.[56]
  • Neonates and Infants with COVID-19 are often asymptomatic or present with fever with or without mild cough and congestion.

Physical Examination

Laboratory Findings

Studies reportedly showed following lab abnormalities in pediatric patients with COVID-19

Electrocardiogram

X-ray

CT scan

CT chest is an important diagnostic modality in pediatric patients with COVID-19. Chest CT scans has reportedly shown higher positive rates in suspected patients than RT-PCR. It has better sensitivity. CT chest and a series of chest X-rays can be used to monitor the progression of the disease. Imaging findings reported in the studies are

Children are at increased risk of radiation and its effects, so CT scans and X-rays should be judiciously used in them. It is advised to perform Pulmonary Ultrasonography (USG) in newborns. It has better sensitivity and is safer than CT scans and Chest X-rays.

MRI

Other Diagnostic Studies

Treatment

Management of COVID-19 in pediatric patients depends on the severity of symptoms.

  • Hospital admission and level of care depend on the clinical presentation, supportive care requirement, underlying comorbidities, and availability of health care facilities at home
  • Suspected patients must be isolated at a hospital or home until the diagnosis is excluded
  • After confirming the diagnosis, they should be hospitalized and isolated in the wards maintained for pediatric patients with COVID-19
  • Critical and severe cases require Intensive Care Unit (ICU) admission and management

As no effective treatment has been approved by the FDA yet, the main goal of managing patients with COVID-19 is to treat the symptoms, provide supportive care, prevent and treat complications, treat underlying diseases and secondary infections, and provide organ function support. Following measures are reported to be crucial in the management of COVID-19[57]

Symptomatic treatment and Supportive Care

Fever should be treated with physical cooling and antipyretics. If the body temperature exceeds 38.5C, antipyretic drugs should be started. Drugs that can be used in children are acetaminophen 10-15 mg/kg and ibuprofen 5-10 mg/kg orally.[57]

Respiratory support

Mechanical Ventilation

Low tidal volume mechanical ventilation is preferred to prevent ventilation related lung injury. Criteria for starting mechanical ventilation[57]

OR

OR

Antibiotics

Antibiotics and antifungals help in reducing symptoms and preventing complications of secondary infections[59]

Corticosteroids

Steroids are used in severe cases and to prevent complications[59]. Any of the following criteria must be met before starting corticosteroid therapy in patients with COVID-19[57]. Intravenous methylprednisolone 1-2mg/kg/day used for 3-5 days. Long-term usage is highly discouraged.

  • Rapid progression of the disease as documented from chest imaging and development of ARDS

OR

OR

OR

Anticoagulation therapy

Convalescent plasma therapy

Evidence suggests the use of plasma therapy in children with exacerbations and severe and critical disease.

Immunoglobulin therapy

  • Intravenous immunoglobulins (IVIG) can be used in severe cases[59]
  • Dose of 1g/kg/day for 2days or 400mg/kg/day for 8 days is recommended for children
  • More studies are required to support its efficacy and safety in children with COVID-19

Antiviral therapy

Following are the experimental drugs that are being considered to treat children with COVID-19[60]. Various clinical trials are being conducted on the efficacy and safety of these drugs in children with COVID-19.

Interferon-alpha

Inhaled interferon-alpha was the most commonly used antiviral in patients with COVID-19. Reports suggest that it helps in decreasing the viral load, alleviating symptoms and shortening the disease course.[61][62]

Remdesivir

  • It is a nucleotide analogue that inhibits viral RNA polymerase
  • It was effectively used during Ebola, SARS, and MERS outbreaks
  • It was effective in-vitro against SARS-CoV-2[63]
  • No adverse effects were reported in a newborn treated for Ebola[64]
  • Phase III clinical trial is being conducted on the effectiveness of Remdesivir in treating COVID-19 in adults and children above 12 years of age[65]
  • FDA has approved the emergency use of Remdesivir in treating hospitalized children with severe disease"Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment | FDA".

Favipiravir


Prevention

Re-opening of schools

  • The pandemic which started in China in January 2020 and now is all over the world has had a tremendous effect on the everyday life of many however children are the most affected.
  • With the peak of the coronavirus cases being over in many countries like the USA and Europe, there is a dilemma for the school officials about when to reopen schools for children.
  • According to the data collected by the CDC[29] and other articles[68][69] children are affected less compared to adults with asymptomatic to mild COVID-19 symptoms.
  • The challenge faced by the school committees around the world is to decide between the pros and cons of whether to reopen the school with children facing the emotional toll of the lockdown and quarantine. [70]

The CDC guidelines for re-opening schools are as follows [71]

  • These guidelines are to be followed by schools by coordinating with the local health department to know the level of mitigation in your community as the coronavirus cases are increasing.
  • Educate the teachers and the parents on signs of coronavirus like dry cough, cold, high fever, and other flu-like symptoms.
  • If the child has the above-mentioned symptoms or is in contact with an adult at home having these symptoms or the adult at home has tested positive the child should stay home.
  • Teachers, children, and other staff members with the immunocompromised state should be given the option to work from home virtually as they are in the high-risk group.
  • Hand hygiene- Soap and water should be provided by the school for students to wash hands frequently for 20 seconds
  • If soap and water are not available provide hand sanitizer with at least 60% alcohol.
  • Use a tissue to cover cough/sneeze and wash hands after discarding the tissue safely.
  • Cloth face mask is advised for all the school staff and the children except kids younger than 2 years of age or kids with a breathing problem who needs assistance in removing the face mask.
  • Signs about COVID 19 should be placed in places frequently visited like the school entrance, cafeteria, and the bathroom.
  • Avoid sharing objects and if possible give kids individual supplies.
  • Ensure proper ventilation systems are in place, open windows when it's safe and possible.
  • Identify small groups of children and try to keep them together with the same teacher.
  • Food brought from home is advisable. If not then food should be distributed in the classroom, not the cafeteria.
  • Advise students and teachers to limit their exposure to the news stories. It can be overwhelming for the students.
  • Encourage the students to talk to anyone they trust or to reach out to teachers to talk when overwhelmed.
  • If a child tests positive or is suspected to have COVID-19 the school should arrange special transport for the student separately.
  • Inform the local health care department and close contacts if the student tests positive.
  • Proper contact tracing, isolation, disinfecting the common places frequently used by the students should be made a priority.

Domestic violence in children

References

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  2. ↑ Lu, Jian; Cui, Jie; Qian, Zhaohui; Wang, Yirong; Zhang, Hong; Duan, Yuange; Wu, Xinkai; Yao, Xinmin; Song, Yuhe; Li, Xiang; Wu, Changcheng; Tang, Xiaolu (2020). "On the origin and continuing evolution of SARS-CoV-2". National Science Review. doi:10.1093/nsr/nwaa036. ISSN 2095-5138.
  3. ↑ Lu, Roujian; Zhao, Xiang; Li, Juan; Niu, Peihua; Yang, Bo; Wu, Honglong; Wang, Wenling; Song, Hao; Huang, Baoying; Zhu, Na; Bi, Yuhai; Ma, Xuejun; Zhan, Faxian; Wang, Liang; Hu, Tao; Zhou, Hong; Hu, Zhenhong; Zhou, Weimin; Zhao, Li; Chen, Jing; Meng, Yao; Wang, Ji; Lin, Yang; Yuan, Jianying; Xie, Zhihao; Ma, Jinmin; Liu, William J; Wang, Dayan; Xu, Wenbo; Holmes, Edward C; Gao, George F; Wu, Guizhen; Chen, Weijun; Shi, Weifeng; Tan, Wenjie (2020). "Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding". The Lancet. 395 (10224): 565–574. doi:10.1016/S0140-6736(20)30251-8. ISSN 0140-6736.
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  6. ↑ Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang; Hu, Ben; Zhang, Lei; Zhang, Wei; Si, Hao-Rui; Zhu, Yan; Li, Bei; Huang, Chao-Lin; Chen, Hui-Dong; Chen, Jing; Luo, Yun; Guo, Hua; Jiang, Ren-Di; Liu, Mei-Qin; Chen, Ying; Shen, Xu-Rui; Wang, Xi; Zheng, Xiao-Shuang; Zhao, Kai; Chen, Quan-Jiao; Deng, Fei; Liu, Lin-Lin; Yan, Bing; Zhan, Fa-Xian; Wang, Yan-Yi; Xiao, Geng-Fu; Shi, Zheng-Li (2020). "A pneumonia outbreak associated with a new coronavirus of probable bat origin". Nature. doi:10.1038/s41586-020-2012-7. ISSN 0028-0836.
  7. ↑ Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W (February 2020). "Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding". Lancet. 395 (10224): 565–574. doi:10.1016/S0140-6736(20)30251-8. PMID 32007145 Check |pmid= value (help).
  8. ↑ Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL (February 2020). "A pneumonia outbreak associated with a new coronavirus of probable bat origin". Nature. doi:10.1038/s41586-020-2012-7. PMID 32015507 Check |pmid= value (help).
  9. ↑ Zhang, Haibo; Penninger, Josef M.; Li, Yimin; Zhong, Nanshan; Slutsky, Arthur S. (2020). "Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target". Intensive Care Medicine. doi:10.1007/s00134-020-05985-9. ISSN 0342-4642.
  10. ↑ Chan, Jasper Fuk-Woo; Yuan, Shuofeng; Kok, Kin-Hang; To, Kelvin Kai-Wang; Chu, Hin; Yang, Jin; Xing, Fanfan; Liu, Jieling; Yip, Cyril Chik-Yan; Poon, Rosana Wing-Shan; Tsoi, Hoi-Wah; Lo, Simon Kam-Fai; Chan, Kwok-Hung; Poon, Vincent Kwok-Man; Chan, Wan-Mui; Ip, Jonathan Daniel; Cai, Jian-Piao; Cheng, Vincent Chi-Chung; Chen, Honglin; Hui, Christopher Kim-Ming; Yuen, Kwok-Yung (2020). "A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster". The Lancet. 395 (10223): 514–523. doi:10.1016/S0140-6736(20)30154-9. ISSN 0140-6736.
  11. ↑ Crackower, Michael A.; Sarao, Renu; Oudit, Gavin Y.; Yagil, Chana; Kozieradzki, Ivona; Scanga, Sam E.; Oliveira-dos-Santos, Antonio J.; da Costa, Joan; Zhang, Liyong; Pei, York; Scholey, James; Ferrario, Carlos M.; Manoukian, Armen S.; Chappell, Mark C.; Backx, Peter H.; Yagil, Yoram; Penninger, Josef M. (2002). "Angiotensin-converting enzyme 2 is an essential regulator of heart function". Nature. 417 (6891): 822–828. doi:10.1038/nature00786. ISSN 0028-0836.
  12. ↑ Danilczyk, Ursula; Sarao, Renu; Remy, Christine; Benabbas, Chahira; Stange, Gerti; Richter, Andreas; Arya, Sudha; Pospisilik, J. Andrew; Singer, Dustin; Camargo, Simone M. R.; Makrides, Victoria; Ramadan, Tamara; Verrey, Francois; Wagner, Carsten A.; Penninger, Josef M. (2006). "Essential role for collectrin in renal amino acid transport". Nature. 444 (7122): 1088–1091. doi:10.1038/nature05475. ISSN 0028-0836.
  13. ↑ Gu, Jiang; Gong, Encong; Zhang, Bo; Zheng, Jie; Gao, Zifen; Zhong, Yanfeng; Zou, Wanzhong; Zhan, Jun; Wang, Shenglan; Xie, Zhigang; Zhuang, Hui; Wu, Bingquan; Zhong, Haohao; Shao, Hongquan; Fang, Weigang; Gao, Dongshia; Pei, Fei; Li, Xingwang; He, Zhongpin; Xu, Danzhen; Shi, Xeying; Anderson, Virginia M.; Leong, Anthony S.-Y. (2005). "Multiple organ infection and the pathogenesis of SARS". The Journal of Experimental Medicine. 202 (3): 415–424. doi:10.1084/jem.20050828. ISSN 1540-9538.
  14. ↑ Ding, Yanqing; He, Li; Zhang, Qingling; Huang, Zhongxi; Che, Xiaoyan; Hou, Jinlin; Wang, Huijun; Shen, Hong; Qiu, Liwen; Li, Zhuguo; Geng, Jian; Cai, Junjie; Han, Huixia; Li, Xin; Kang, Wei; Weng, Desheng; Liang, Ping; Jiang, Shibo (2004). "Organ distribution of severe acute respiratory syndrome(SARS) associated coronavirus(SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways". The Journal of Pathology. 203 (2): 622–630. doi:10.1002/path.1560. ISSN 0022-3417.
  15. ↑ Hamming, I; Timens, W; Bulthuis, MLC; Lely, AT; Navis, GJ; van Goor, H (2004). "Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis". The Journal of Pathology. 203 (2): 631–637. doi:10.1002/path.1570. ISSN 0022-3417.
  16. ↑ Wang, Dawei; Hu, Bo; Hu, Chang; Zhu, Fangfang; Liu, Xing; Zhang, Jing; Wang, Binbin; Xiang, Hui; Cheng, Zhenshun; Xiong, Yong; Zhao, Yan; Li, Yirong; Wang, Xinghuan; Peng, Zhiyong (2020). "Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China". JAMA. doi:10.1001/jama.2020.1585. ISSN 0098-7484.
  17. ↑ Huang, Chaolin; Wang, Yeming; Li, Xingwang; Ren, Lili; Zhao, Jianping; Hu, Yi; Zhang, Li; Fan, Guohui; Xu, Jiuyang; Gu, Xiaoying; Cheng, Zhenshun; Yu, Ting; Xia, Jiaan; Wei, Yuan; Wu, Wenjuan; Xie, Xuelei; Yin, Wen; Li, Hui; Liu, Min; Xiao, Yan; Gao, Hong; Guo, Li; Xie, Jungang; Wang, Guangfa; Jiang, Rongmeng; Gao, Zhancheng; Jin, Qi; Wang, Jianwei; Cao, Bin (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". The Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. ISSN 0140-6736.
  18. ↑ Guan, Wei-jie; Ni, Zheng-yi; Hu, Yu; Liang, Wen-hua; Ou, Chun-quan; He, Jian-xing; Liu, Lei; Shan, Hong; Lei, Chun-liang; Hui, David SC; Du, Bin; Li, Lan-juan; Zeng, Guang; Yuen, Kowk-Yung; Chen, Ru-chong; Tang, Chun-li; Wang, Tao; Chen, Ping-yan; Xiang, Jie; Li, Shi-yue; Wang, Jin-lin; Liang, Zi-jing; Peng, Yi-xiang; Wei, Li; Liu, Yong; Hu, Ya-hua; Peng, Peng; Wang, Jian-ming; Liu, Ji-yang; Chen, Zhong; Li, Gang; Zheng, Zhi-jian; Qiu, Shao-qin; Luo, Jie; Ye, Chang-jiang; Zhu, Shao-yong; Zhong, Nan-shan (2020). doi:10.1101/2020.02.06.20020974. Missing or empty |title= (help)
  19. ↑ 19.0 19.1 Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, Li T, Chen Q (February 2020). "High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa". Int J Oral Sci. 12 (1): 8. doi:10.1038/s41368-020-0074-x. PMC 7039956 Check |pmc= value (help). PMID 32094336 Check |pmid= value (help).
  20. ↑ Zhang, Haibo; Penninger, Josef M.; Li, Yimin; Zhong, Nanshan; Slutsky, Arthur S. (2020). "Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target". Intensive Care Medicine. doi:10.1007/s00134-020-05985-9. ISSN 0342-4642.
  21. ↑ Kasumba DM, Grandvaux N (February 2019). "Therapeutic Targeting of RIG-I and MDA5 Might Not Lead to the Same Rome". Trends Pharmacol. Sci. 40 (2): 116–127. doi:10.1016/j.tips.2018.12.003. PMC 7112877 Check |pmc= value (help). PMID 30606502.
  22. ↑ Huang, Chaolin; Wang, Yeming; Li, Xingwang; Ren, Lili; Zhao, Jianping; Hu, Yi; Zhang, Li; Fan, Guohui; Xu, Jiuyang; Gu, Xiaoying; Cheng, Zhenshun; Yu, Ting; Xia, Jiaan; Wei, Yuan; Wu, Wenjuan; Xie, Xuelei; Yin, Wen; Li, Hui; Liu, Min; Xiao, Yan; Gao, Hong; Guo, Li; Xie, Jungang; Wang, Guangfa; Jiang, Rongmeng; Gao, Zhancheng; Jin, Qi; Wang, Jianwei; Cao, Bin (2020). "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China". The Lancet. 395 (10223): 497–506. doi:10.1016/S0140-6736(20)30183-5. ISSN 0140-6736.
  23. ↑ Velavan, Thirumalaisamy P.; Meyer, Christian G. (2020). "The COVID‐19 epidemic". Tropical Medicine & International Health. 25 (3): 278–280. doi:10.1111/tmi.13383. ISSN 1360-2276.
  24. ↑ Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, Law KI, Tang BS, Hon TY, Chan CS, Chan KH, Ng JS, Zheng BJ, Ng WL, Lai RW, Guan Y, Yuen KY (May 2003). "Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study". Lancet. 361 (9371): 1767–72. doi:10.1016/s0140-6736(03)13412-5. PMID 12781535.
  25. ↑ Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, Chu CM, Hui PK, Mak KL, Lim W, Yan KW, Chan KH, Tsang NC, Guan Y, Yuen KY, Peiris JS (May 2003). "Lung pathology of fatal severe acute respiratory syndrome". Lancet. 361 (9371): 1773–8. doi:10.1016/s0140-6736(03)13413-7. PMID 12781536.
  26. ↑ Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, Lit LC, Hui DS, Chan MH, Chung SS, Sung JJ (April 2004). "Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome". Clin. Exp. Immunol. 136 (1): 95–103. doi:10.1111/j.1365-2249.2004.02415.x. PMC 1808997. PMID 15030519.
  27. ↑ 27.0 27.1 Velavan, Thirumalaisamy P.; Meyer, Christian G. (2020). "The COVID‐19 epidemic". Tropical Medicine & International Health. 25 (3): 278–280. doi:10.1111/tmi.13383. ISSN 1360-2276.
  28. ↑ Rothan, Hussin A.; Byrareddy, Siddappa N. (2020). "The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak". Journal of Autoimmunity: 102433. doi:10.1016/j.jaut.2020.102433. ISSN 0896-8411.
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 29.6 29.7 29.8 29.9 Stokes EK, Zambrano LD, Anderson KN, Marder EP, Raz KM, El Burai Felix S; et al. (2020). "Coronavirus Disease 2019 Case Surveillance - United States, January 22-May 30, 2020". MMWR Morb Mortal Wkly Rep. 69 (24): 759–765. doi:10.15585/mmwr.mm6924e2. PMC 7302472 Check |pmc= value (help). PMID 32555134 Check |pmid= value (help).
  30. ↑ <Castagnoli R, Votto M, Licari A, et al. Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents - a systematic review. JAMA Pediatr Rev. 2020. 10.1001/jamapediatrics.2020.1467>
  31. ↑ <Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020. 10.1542/peds.2020-0702>
  32. ↑ <Castagnoli R, Votto M, Licari A, et al. Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents - a systematic review. JAMA Pediatr Rev. 2020. 10.1001/jamapediatrics.2020.1467>
  33. ↑ <Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020. 10.1542/peds.2020-0702>
  34. ↑ <http://dx.doi.org/10.15585/mmwr.mm6924e2>
  35. ↑ <https://www.niaid.nih.gov/news-events/study-determine-incidence-novel-coronavirus-infection-us-children-begins>
  36. ↑ <Castagnoli R, Votto M, Licari A, et al. Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents - a systematic review. JAMA Pediatr Rev. 2020. 10.1001/jamapediatrics.2020.1467>
  37. ↑ <Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020. 10.1542/peds.2020-0702>
  38. ↑ <http://dx.doi.org/10.15585/mmwr.mm6924e2>
  39. ↑ <https://www.cdc.gov/coronavirus/2019-ncov/covid-data/covidview/index.html>
  40. ↑ <https://coronavirus.jhu.edu/map.html
  41. ↑ <https://coronavirus.jhu.edu/map.html
  42. ↑ <Hui DS, Zumla A. Severe Acute Respiratory Syndrome: Historical, Epidemiologic, and Clinical Features. Infectious Disease Clinics. 2019 Dec 1;33(4):869-89>
  43. ↑ Rasmussen SA, Smulian JC, Lednicky JA, Wen TS, Jamieson DJ (2020). "Coronavirus Disease 2019 (COVID-19) and pregnancy: what obstetricians need to know". Am J Obstet Gynecol. 222 (5): 415–426. doi:10.1016/j.ajog.2020.02.017. PMC 7093856 Check |pmc= value (help). PMID 32105680 Check |pmid= value (help).
  44. ↑ 44.0 44.1 44.2 Mahyuddin AP, Kanneganti A, Wong J, Dimri PS, Su LL, Biswas A; et al. (2020). "Mechanisms and evidence of vertical transmission of infections in pregnancy including SARS-CoV-2". Prenat Diagn. doi:10.1002/pd.5765. PMC 7307070 Check |pmc= value (help). PMID 32529643 Check |pmid= value (help).
  45. ↑ <https://www.cdc.gov/coronavirus/2019-ncov/hcp/care-for-breastfeeding-women.html>
  46. ↑ Zamaniyan M, Ebadi A, Aghajanpoor S, Rahmani Z, Haghshenas M, Azizi S (2020). "Preterm delivery, maternal death, and vertical transmission in a pregnant woman with COVID-19 infection". Prenat Diagn. doi:10.1002/pd.5713. PMC 7264605 Check |pmc= value (help). PMID 32304114 Check |pmid= value (help).
  47. ↑ Zeng H, Xu C, Fan J, Tang Y, Deng Q, Zhang W; et al. (2020). "Antibodies in Infants Born to Mothers With COVID-19 Pneumonia". JAMA. doi:10.1001/jama.2020.4861. PMC 7099444 Check |pmc= value (help). PMID 32215589 Check |pmid= value (help).
  48. ↑ Dong L, Tian J, He S, Zhu C, Wang J, Liu C; et al. (2020). "Possible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn". JAMA. doi:10.1001/jama.2020.4621. PMC 7099527 Check |pmc= value (help). PMID 32215581 Check |pmid= value (help).
  49. ↑ Chen, Nanshan; Zhou, Min; Dong, Xuan; Qu, Jieming; Gong, Fengyun; Han, Yang; Qiu, Yang; Wang, Jingli; Liu, Ying; Wei, Yuan; Xia, Jia'an; Yu, Ting; Zhang, Xinxin; Zhang, Li (2020). "Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study". The Lancet. 395 (10223): 507–513. doi:10.1016/S0140-6736(20)30211-7. ISSN 0140-6736.
  50. ↑ "[Diagnosis and clinical management of 2019 novel coronavirus infection: an operational recommendation of Peking Union Medical College Hospital (V2.0)]". Zhonghua Nei Ke Za Zhi (in Chinese). 59 (3): 186–188. February 2020. doi:10.3760/cma.j.issn.0578-1426.2020.03.003. PMID 32023681 Check |pmid= value (help).
  51. ↑ 51.0 51.1 Belhadjer, Zahra; Méot, Mathilde; Bajolle, Fanny; Khraiche, Diala; Legendre, Antoine; Abakka, Samya; Auriau, Johanne; Grimaud, Marion; Oualha, Mehdi; Beghetti, Maurice; Wacker, Julie; Ovaert, Caroline; Hascoet, Sebastien; Selegny, Maëlle; Malekzadeh-Milani, Sophie; Maltret, Alice; Bosser, Gilles; Giroux, Nathan; Bonnemains, Laurent; Bordet, Jeanne; Di Filippo, Sylvie; Mauran, Pierre; Falcon-Eicher, Sylvie; Thambo, Jean-Benoît; Lefort, Bruno; Moceri, Pamela; Houyel, Lucile; Renolleau, Sylvain; Bonnet, Damien (2020). "Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic". Circulation. doi:10.1161/CIRCULATIONAHA.120.048360. ISSN 0009-7322.
  52. ↑ <Posttraumatic stress disorder (PTSD) in parents and youth after health-related disasters. Sprang G, Silman M Disaster Med Public Health Prep. 2013 Feb; 7(1):105-10.>
  53. ↑ 53.0 53.1 Chen ZM, Fu JF, Shu Q, Chen YH, Hua CZ, Li FB; et al. (2020). "Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus". World J Pediatr. 16 (3): 240–246. doi:10.1007/s12519-020-00345-5. PMC 7091166 Check |pmc= value (help). PMID 32026148 Check |pmid= value (help).
  54. ↑ Diotallevi, Federico; Campanati, Anna; Bianchelli, Tommaso; Bobyr, Ivan; Luchetti, Michele Maria; Marconi, Barbara; Martina, Emanuela; Radi, Giulia; Offidani, Annamaria (2020). "Skin involvement in SARS‐CoV‐2 infection: Case series". Journal of Medical Virology. doi:10.1002/jmv.26012. ISSN 0146-6615.
  55. ↑ Andina, David; Noguera‐Morel, Lucero; Bascuas‐Arribas, Marta; Gaitero‐Tristán, Jara; Alonso‐Cadenas, José Antonio; Escalada‐Pellitero, Silvia; Hernández‐Martín, Ángela; Torre‐Espi, Mercedes; Colmenero, Isabel; Torrelo, Antonio (2020). "Chilblains in children in the setting of COVID‐19 pandemic". Pediatric Dermatology. 37 (3): 406–411. doi:10.1111/pde.14215. ISSN 0736-8046.
  56. ↑ Dugue, Rachelle; Cay-Martínez, Karla C.; Thakur, Kiran T.; Garcia, Joel A.; Chauhan, Lokendra V.; Williams, Simon H.; Briese, Thomas; Jain, Komal; Foca, Marc; McBrian, Danielle K.; Bain, Jennifer M.; Lipkin, W. Ian; Mishra, Nischay (2020). "Neurologic manifestations in an infant with COVID-19". Neurology. 94 (24): 1100–1102. doi:10.1212/WNL.0000000000009653. ISSN 0028-3878.
  57. ↑ 57.0 57.1 57.2 57.3 Shen K, Yang Y, Wang T, Zhao D, Jiang Y, Jin R; et al. (2020). "Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts' consensus statement". World J Pediatr. doi:10.1007/s12519-020-00343-7. PMC 7090771 Check |pmc= value (help). PMID 32034659 Check |pmid= value (help).
  58. ↑ Sankar J, Dhochak N, Kabra SK, Lodha R (2020). "COVID-19 in Children: Clinical Approach and Management". Indian J Pediatr. 87 (6): 433–442. doi:10.1007/s12098-020-03292-1. PMC 7183927 Check |pmc= value (help). PMID 32338347 Check |pmid= value (help).
  59. ↑ 59.0 59.1 59.2 Zhang L, Peres TG, Silva MVF, Camargos P (2020). "What we know so far about Coronavirus Disease 2019 in children: A meta-analysis of 551 laboratory-confirmed cases". Pediatr Pulmonol. doi:10.1002/ppul.24869. PMC 7300763 Check |pmc= value (help). PMID 32519809 Check |pmid= value (help).
  60. ↑ Deniz M, Tapısız A, Tezer H (2020). "Drugs being investigated for children with COVID-19". Acta Paediatr. doi:10.1111/apa.15399. PMC 7300686 Check |pmc= value (help). PMID 32506621 Check |pmid= value (help).
  61. ↑ Wang BX, Fish EN (2019). "Global virus outbreaks: Interferons as 1st responders". Semin Immunol. 43: 101300. doi:10.1016/j.smim.2019.101300. PMC 7128104 Check |pmc= value (help). PMID 31771760.
  62. ↑ Chen L, Shi M, Deng Q, Liu W, Li Q, Ye P; et al. (2020). "Correction: A multi-center randomized prospective study on the treatment of infant bronchiolitis with interferon α1b nebulization". PLoS One. 15 (4): e0231911. doi:10.1371/journal.pone.0231911. PMC 7147733 Check |pmc= value (help). PMID 32275690 Check |pmid= value (help).
  63. ↑ Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A; et al. (2020). "Compassionate Use of Remdesivir for Patients with Severe Covid-19". N Engl J Med. 382 (24): 2327–2336. doi:10.1056/NEJMoa2007016. PMC 7169476 Check |pmc= value (help). PMID 32275812 Check |pmid= value (help).
  64. ↑ Dörnemann J, Burzio C, Ronsse A, Sprecher A, De Clerck H, Van Herp M; et al. (2017). "First Newborn Baby to Receive Experimental Therapies Survives Ebola Virus Disease". J Infect Dis. 215 (2): 171–174. doi:10.1093/infdis/jiw493. PMC 5583641. PMID 28073857.
  65. ↑ Campbell CH (1967). "Effect of incubation temperature and serum content in agar overlay on plaque production by foot-and-mouth disease virus". Can J Comp Med Vet Sci. 31 (10): 251–5. PMC 1494743. PMID 04292899.
  66. ↑ 66.0 66.1 Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J; et al. (2020). "Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study". Engineering (Beijing). doi:10.1016/j.eng.2020.03.007. PMC 7185795 Check |pmc= value (help). PMID 32346491 Check |pmid= value (help).
  67. ↑ 67.0 67.1 Bouazza N, Treluyer JM, Foissac F, Mentré F, Taburet AM, Guedj J; et al. (2015). "Favipiravir for children with Ebola". Lancet. 385 (9968): 603–604. doi:10.1016/S0140-6736(15)60232-X. PMID 25706078.
  68. ↑ <Castagnoli R, Votto M, Licari A, et al. Severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents - a systematic review. JAMA Pediatr Rev. 2020. 10.1001/jamapediatrics.2020.1467>
  69. ↑ <Dong Y, Mo X, Hu Y, et al. Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China. Pediatrics. 2020. 10.1542/peds.2020-0702>
  70. ↑ Fantini MP, Reno C, Biserni GB, Savoia E, Lanari M (2020). "COVID-19 and the re-opening of schools: a policy maker's dilemma". Ital J Pediatr. 46 (1): 79. doi:10.1186/s13052-020-00844-1. PMC 7280677 Check |pmc= value (help). PMID 32517815 Check |pmid= value (help).
  71. ↑ <https://www.cdc.gov/coronavirus/2019-ncov/community/schools-childcare/schools.html>
  72. ↑ Bressan S, Gallo E, Tirelli F, Gregori D, Da Dalt L (2020). "Lockdown: more domestic accidents than COVID-19 in children". Arch Dis Child. doi:10.1136/archdischild-2020-319547. PMID 32487724 Check |pmid= value (help).
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