Version 2.2-June 1, 2020

CHILDREN’S HOSPITAL OF THE KING’S DAUGHTERS

CHKD Treatment Guideline for COVID-19 in Children

***This guideline will be frequently updated, ensure the you are utilizing the most recent version***

Patient population: Patients with suspected or confirmed COVID-19 infection, who are admitted to an inpatient floor or the intensive

care unit.

Clinical symptoms: Range from uncomplicated upper respiratory tract viral infection to pneumonia, acute respiratory distress

syndrome (ARDS), sepsis, and septic shock (Table 1). No specific data is available establishing risk factors for severe COVID-19

disease in children.23 In addition, a rare but serious inflammatory syndrome in children has been linked to COVID-19. The CDC is calling the condition multisystem inflammatory syndrome in children (MIS-C).25-26

COVID-19 Treatment:

Supportive Therapy: Supportive treatment including sufficient fluid and calorie intake, and additional oxygen supplementation should be used in the treatment of children infected with COVID-19. The aim is to prevent ARDS, organ

failure, and secondary nosocomial infections. If bacterial infection is suspected, broad-spectrum antibiotics may be used.22

NSAID use is not contraindicated and has not been proven to have any added benefit or adverse outcomes in patients with

COVID-19.

Antiviral Therapy: Currently, no drug has been proven to be safe and effective for treating COVID-19. There is insufficient data to recommend either for or against the use of any antiviral or immunomodulatory therapy in patients with COVID-19

who have mild, moderate, severe, or critical illness. Treatment should be considered as outlined in (Figure 1). All

medications described in (Table 4) are considered investigational or expanded access/EUA. The decision to use these

medications should be made only after assessing the risks and benefits in addition to clinical status, comorbidities, and

interacting medications.22-23 No drugs have been found to be effective and are not recommended by the COVID-19 Treatment

Guidelines.23 An informed consent should be reviewed and completed prior to treatment.

Anticoagulation: COVID-19 is associated with an increased risk of venous thromboembolism (VTE) in adults. Due to this risk, routine use of pharmacologic prophylaxis or therapeutic anticoagulation is utilized unless contraindicated. Currently there are no

specific recommendations for pediatric patients with COVID-19.15-21 Pediatric confirmed COVID-19 hospitalized patients should be

assessed based on risk factors as outlined below:

1) Consider Heme/Onc consult for risk assessment and recommendations

2) Individual VTE risk factors should be evaluated on admission and reassessed every 48-72 hours for the duration of the hospitalization

3) Enoxaparin prophylaxis is recommended in adult patients with confirmed COVID-19 unless contraindicated 4) Enoxaparin prophylaxis should be strongly considered in pediatric patients with confirmed COVID-19 unless

contraindicated 5) An assessment of bleeding risks verse benefit should be completed on each patient (Table 2.) 6) Alternative methods of prophylaxis, such as early ambulation or mechanical prophylaxis should be considered in

contraindicated patients and all COVID-19 pediatric patients, if applicable. 15-21

Multisystem Inflammatory Syndrome in Children (MIS-C): Recent reports describe a rare but serious COVID-19 associated

syndrome in children referred to as MIS-C.24-25 MIS-C consists of persistent fever, elevated inflammatory markers (including cytokine

storm), neutrophilia, lymphopenia, coagulopathy and a variety of clinical manifestations including:

a) Vasodilatory shock with normal or mildly depressed systolic function b) Cardiogenic shock with ≥ moderate systolic dysfunction c) Kawasaki disease (KD) features (can be complete or incomplete KD) d) Clinical and laboratory features of cytokine storm e) Coronary artery dilation and aneurysms (up to 25% of children and teens with MIS-C26) f) Any combination of the above

Not all patients present with respiratory symptoms and/or a (+) COVID-19 test via RT-PCR or serology.24-26 The CDC recommends

providers report any patient who meets the case definition (see below) to local, state, and territorial health departments. Some individuals may fulfill full or partial criteria for Kawasaki disease but should be reported if they meet the case definition for MIS-C.24-

26 If a patient presents with a classic KD and incidentally found to be COVID-19 (+), treat as standard KD. Patients who present with

COVID-19 + HLH, Heme-Onc should be consulted for recommendations. Infectious disease and/or rheumatology should be consulted

to assist with management in addition to the specific treatment and management recommendations outlined in (Figure 3.)

Version 2.2-June 1, 2020

MIS-C Case Definition in Children24: Patients present with ALL:

a) Age 2) organ involvement [cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurologic]

b) No alternative plausible diagnoses c) Positive for current or recent COVID-19 infection or COVID-19 exposure within the 4 weeks prior to the onset of symptoms

Table 1. Clinical symptoms associated with COVID-19 infection

Source: World Health Organization

Table 2. Bleeding Risk Factors: 15-21

Increased Decreased

CRP

ESR

Ferritin

Procalcitonin

LDH

IL-6

Neutrophils

Troponin

VBG w/ Lactate

LDH

D-Dimer

Lymphocytes

Albumin

Symptoms Description

Uncomplicated Illness

Uncomplicated upper respiratory tract viral infection with nonspecific symptoms including:

Fever, cough, sore throat, nasal congestion, malaise, headache, muscle pain Without signs of dehydration, sepsis, or shortness of breath

Mild Pneumonia Non-severe pneumonia presenting with cough or difficulty breathing +tachypnea

Without signs of severe pneumonia

Severe Pneumonia Diagnosis is clinical

Adolescent: fever or suspected respiratory infection + one of the below:

RR > 30 breaths/min

Severe respiratory distress

SpO2 < 90% on room air Child: cough of difficulty breathing + one of the below:

Central cyanosis

SpO2 < 90%

Severe respiratory distress

Clinical signs of pneumonia + inability to breast feed or drink, lethargy, convulsions

ARDS

New or worsening respiratory symptoms within one week of known clinical insult

Chest imaging consistent with ARDS

Respiratory failure not explained by cardiac failure or fluid overload

Sepsis Diagnosis made clinically

Septic Shock Diagnosis made clinically

Bleeding Risk Factors Description

Not Recommended Intracranial hemorrhage

Active bleed

Consider with caution

Intracranial mass

Lumbar puncture w/in 24 hours

Coagulopathy

Neurosurgical procedure w/in 24 hours

Version 2.2-June 1, 2020

Figure 1. Treatment Algorithm in Children: Dosing per (Table 4)

Evaluate Remdesivir Eligibility:

Refer to CHKD Remdesivir policy

Policy located on COVID-19 kdnet

If eligible, Consult ID£ ASAP to initiate process

ID will guide on interim treatment

NOT Mechanically Ventilated

Outpatient Otherwise healthy child with suspected COVID19

Including High Risk*

Awaiting COVID19 results Supportive Care ONLY

Confirmed (+) COVID19 test Supportive Care

ONLY

Inpatient: Non-ICU Otherwise healthy child with suspected COVID19 + clinical symptoms including:

Uncomplicated illness

Mild Pneumonia

Awaiting COVID19 results Supportive Care

ONLY

Confirmed (+) COVID19 test Supportive Care ONLY

Inpatient Non-ICU: High Risk* COVID19 + clinical symptoms including:

Mild Pneumonia

Consider baseline and daily interleukin levels

* High Risk- Immunocompromised, cardiovascular, pulmonary, hepatic, renal, hematologic, neurologic conditions

Evaluate QTc prolongation risk (Figure 2) Ψ Shipment requires 1-3 days

£ ID will provide specific 2nd line treatment recommendations, if indicated ** Or other biologic (See Figure 3 or Table 4)

Awaiting COVID19 results

Confirmed (+) COVID19 test

Supportive Care

Supportive Care

Inpatient (PICU/NICU) COVID19 + clinical symptoms including:

Severe Pneumonia

ARDS

Sepsis/Septic Shock

Consider baseline and daily interleukin levels

Awaiting COVID19 results

Confirmed (+) COVID19 test

Supportive Care + ID Consult £

Supportive Care + ID Consult £

High risk of severe disease +

High risk of cytokine storm

OR Rapidly worsening gas exchange

+ Pulmonary infiltrates

+ SpO2 ≤ 93% on RA or > 6L/min

Supportive Care + Consider Tocilizumab**

Remdesivir Approved Remdesivir Excluded

Supportive Care + Remdesivir Ψ+

Consider Tocilizumab**

Mechanically Ventilated

MIS

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Version 2.2-June 1, 2020

Table 4. Agents under investigation for treatment of COVID-19:

1st Line Therapy Dosing & Duration Comments

Remdesivir*

(IV only)

Follow QT evaluation (Figure 2) if combination therapy

Refer to CHKD Remdesivir Policy

Expanded Access Inclusion Criteria:

ONLY: Pregnant women or age < 18 yrs

a) Hospitalized b) Confirmed SARS-CoV-2 by PCR c) Mechanically ventilated

Exclusion Criteria

a) Evidence of multi-organ failure b) Vasopressor requirement c) ALT levels > 5x ULM d) CrCl< 30 mL/min, dialysis or CVVH e) Use in conjunction with another

investigational therapy

Restricted to Infectious Disease

Contact ID ASAP if considering treatment

Adult dosing:

200 mg load, then 100 mg q24h

Pediatric dosing*: Weight LD (once) MD (q24h)

300 ug/L with doubling in 24 hr

Ferritin +

LDH

>600 ug/L at presentation >250

D-dimer Elevated

Adult Dosing (≥18 years):

8 mg/kg X 1 (Max 800 mg)

Pediatric Dosing (1 biologic is not recommended

Avoid live viral vaccines

Caution converting from tocilizumab (longer half-

life) to anakinra *Pediatric dosing obtained via WHO treatment of pediatric Ebola virus TdP: Torsades de pointes

Do not use: oseltamivir, baloxavir, interferon, ribavirin

Version 2.2-June 1, 2020

Medications with Unclear Place in Therapy Consult ID to evaluate possible benefit of the below

Dosing & Duration Comments

Hydroxychloroquine 31

(PO only)

Must evaluate risk vs benefit

Questionable benefit

Follow QT evaluation (Figure 2) if combination therapy

Adult dosing (≥18 years):

400mg BID x 2 doses (load) day 1, then 200 mg BID days 2-5

Pediatric dosing9 ( 50Adult 400mg BID 200 mg BID

LD-Loading Dose

MD-Maintenance Dose

Duration:

5 days

Extended ventilation or profound immunosuppression duration may be

extended

Adverse events:

Retinopathy rash, nausea, glucose fluctuations, and diarrhea. GI symptoms

May be mitigated by taking with food

Use with caution in diabetic patients; hypoglycemia may occur

QT prolongation (known TdP Risk)

G6PD testing: Recommended

Risk of hemolysis is very low

May start while awaiting G6PD results

Additional Comments:

Suspension may be given via NG tube

Separate from antacids by at least 4 hours

May be crushed

Fetal ocular toxicity in animal studies

Excreted into breast milk

Infectious Disease Restricted

ID approval prior to administration

Non-COVID related indications are excluded

If an order is entered it will NOT be verified by a

pharmacist until ID approval is confirmed and

documented

The ordering provider should page ID to obtain

approval once the identified patient meets

requirements for treatment. Documentation of

approval may occur via:

a. Verbal confirmation of ID attending approval, date/time, from the ordering provider

b. Direct confirmation of approval from the ID

attending to the pharmacist

c. If ID approval is not obtained or is rejected,

hydroxychloroquine cannot be verified or

dispensed

The pharmacists will document the approving ID

attending, date, and time on the active order

Azithromycin

(IV/PO)

Studied in combination with hydroxychloroquine with little to no

clinical benefit

Must evaluate risk vs benefit

Follow QT evaluation (Figure 2)

Pediatric dosing (

Version 2.2-June 1, 2020

TdP: Torsades de pointes

MIS-C Specific Therapy Dosing & Duration Comments

IVIG

(IV)

KD features and/or coronary artery

changes

Dosing:

2 g/kg, (max dose 100g)26

Adverse events:

Infusion reactions

Anaphylaxis

Transaminitis,

Aseptic meningitis

Hemolysis

Anakinra

(SQ/IV)

Non-formulary-limited supply

IL-1 Inhibitor

Consider if fevers > 24 hrs post

steroids/IVIG or moderate/severe

presentation

ID Consult Required

Discuss Dosing with ID or Rheum

Range: 2-10 mg/kg/day SQ (Max 100 mg/dose or 10 mg/kg/day) 26,30

Mild MIS-C:

Not Indicated

Moderate MIS-C:

2mg/kg/dose SQ once daily x 5 days (Max 100mg/dose)

Severe MIS-C:

2mg/kg/dose q6h X 1 day then 2mg/kg/dose SQ daily for 4 days (Max

100mg/dose)

Treatment with >1 biologic is not recommended

Avoid live viral vaccines

Short half-life –may convert to tocilizumab without

concern

Caution converting from tocilizumab(longer half-

life) to anakinra

Tocilizumab

Consider for MIS-C if fevers > 24 hrs post steroids/IVIG or moderate/severe

presentation

Refer to above

Corticosteroids

(IV/PO) prednisone, prednisolone, methylprednisolone

Consider for high-risk KD features

MIS-C

Consider for ARDS

Dosing:

2 mg/kg/day divided q8-q12h

Pulse dosing:

10 mg/kg-30 mg/kg/day for 1-3 days

followed by 2 mg/kg/day divided followed

by a taper

Determine based on patient severity

Adverse events:

Hypertension

Hyperglycemia

Version 2.2-June 1, 2020

Figure 2. Management of QT risk with COVID-19 Drugs

.J Interv Card Electrophysiol (2020)

Version 2.2-June 1, 2020

Figure 3. MIS-C Treatment: Dosing see (Table 4.)

Refer to CHKD MIS-C Guideline on Kdnet Presentation (mild, moderate, severe) not well defined and may be subjective see (Table 5.) for guidance

¥ Caution use if overlapping features of HLH due to ↑ clotting risk

* Taper steroids

∞ Guidance on presentation severity see (Table 5.)

Table 5. Presentation Classification Guidance

Treatment Dosing

Steroids 2 mg/kg/day*

IVIG ¥ 2 g/kg, max dose 100g

Biologics Not Indicated unless worsening

Treatment Dosing

Steroids Consider pulse dose X 3 days then,

2 mg/kg/day*

IVIG ¥ 2 g/kg, max dose 100g

Biologics Consider adding tocilizumab, anakinra, or infliximab

Presentation Description

Mild

Requires minimal to no respiratory support

No vasoactive requirements

Minimal to no organ injury

Does not require ICU admission

Severe

Significant oxygen requirement (HFNC, BiPAP, mechanical ventilation)

Mild-Severe organ injury and/or ventricular dysfunction

(+/-) Vasoactive requirement

ICU admission

Patient meets MIS-C Case Criteria

Low Dose Aspirin Recommended in all MIS-C patients, not on other anticoagulation

Consider enoxaparin prophylaxis

Mild Presentation∞ Severe Presentation∞

Consult Infectious Disease

Version 2.2-June 1, 2020

References:

1. Wang, M, Ruiyuan C, Leike Z et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020 30;269-271. 3.

2. Yao X, Fei Y, Miao Z, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020[Online ahead of print].

3. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID19 associated pneumonia

in clinical studies. Biosci Trends, 14 (1), 72-73. 2020 Mar 16. 5.

4. Colson P, Rolain JM, Lagier JC et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID19. Int J of Antimicrob

Agents, 105932. 2020 Mar 4[Online ahead of print].

5. Chu CM et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 59 (3), 252-6. Mar

2004.

6. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a

retrospective cohort study. Lancet. 2020 Mar 11[Online ahead of print].

7. Xia W, Shao J, Guo Y, et al. Clinical and CT features in pediatric patients with COVID‐19 infection: Different points from adults. Pediatric

Pulmonology. 2020 Mar 5[Online ahead of print].

8. Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐

randomized clinical trial. International Journal of Antimicrobial Agents – In Press 17 March 2020

DOI: 10.1016/j.ijantimicag.2020.105949

9. Michael Cohen-Wolkowiez, MD PhD; Anil Maharaj, PhD; Huali Wu, PhD, et al. Pediatric Trials Network (PTN) Hydroxychloroquine

Pediatric Dosing Guidelines to Target Treatment of SARS-CoV-2 Virus. 20 March, 2020

10. Giwa AL, Desai A, Duca A. Novel 2019 coronavirus SARS-CoV-2 (COVID-19): An updated overview for emergency clinicians. Emerg Med Pract. 2020 May 1;22(5):1-28. Epub 2020 Mar 24

11. Chen C, Zhang XR, Ju ZY, et al. Advances in the research of cytokine storm mechanism induced by corona virus disease 2019 and the

corresponding Go to www.ebmedicine.net/COVID-19 for updates to this article, podcasts and videos, and more immunotherapies.

Zhonghua Shao Shang Za Zhi 2020;36:E005-E005 (Basic science review)

12. Yonggang Zhou BF, Xiaohu Zheng et al. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19

patients. 2020

13. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet

14. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a

retrospective cohort study. Lancet (London, England) 2020:S0140-6736(0120)30566-30563 (Retrospective cohort study; 191 patients)

15. Meier KA, Clark E, Tarango C, Chima RS, Shaughnessy E. Venous thromboembolism in hospitalized adolescents: an approach to risk

assessment and prophylaxis. Hospital pediatrics. 2015;5(1):44-51

16. Newall F, Branchford B, Male C. Anticoagulant prophylaxis and therapy in children: current challenges and emerging issues. Journal of

thrombosis and haemostasis : JTH. 2018;16(2):196-208

17. Mahajerin A, Webber EC, Morris J, Taylor K, Saysana M. Development and Implementation Results of a Venous Thromboembolism

Prophylaxis Guideline in a Tertiary Care Pediatric Hospital. Hospital pediatrics. 2015;5(12):630-636

18. Hanson SJ, Punzalan RC, Arca MJ, et al. Effectiveness of clinical guidelines for deep vein thrombosis prophylaxis in reducing the

incidence of venous thromboembolism in critically ill children after trauma. The journal of trauma and acute care surgery.

2012;72(5):1292-1297

19. Faustino EV, Raffini LJ. Prevention of Hospital-Acquired Venous Thromboembolism in Children: A Review of Published Guidelines.

Frontiers in pediatrics. 2017;5:9

20. Kim SJ, Sabharwal S. Risk factors for venous thromboembolism in hospitalized children and adolescents: a systemic review and pooled

analysis. Journal of pediatric orthopedics Part B. 2014;23(4):389-393

21. Parasuraman S., Goldhaber S. Venous Thromboembolism in Children. Circulation. 2006;113:e12-e16 22. Zimmerman P., Curtis N. Coronavirus Infections in Children Including COVID-19: An Overview of the Epidemiology, Clinical Features,

Diagnosis, Treatment and Prevention Options in Children. Pediatr Infect Dis J. 2020;XX:00–00

23. Panel on COVID-19 Treatment. COVID-19 Treatment Guidelines. Available at https://www.covid19treatmentguidelines.nih.gov/overview/ Accessed (5/2020)

24. CDC details COVID-19-related inflammatory syndrome in children, AAP News, Accessed (5/2020)

25. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19). Distributed via the

CDC Health Alert Network, May 14, 2020, 4:45 PM ET, CDCHAN-00432

26. Boston Children’s PMIS COVID-19 Evaluation and Management Protocol, Accessed (5/2020)

27. Royal College of Paediatrics and Child Health Guidance: Paediatric multisystem inflammatory syndrome temporally associated with

COVID-19

28. Riphagen S, Gomez X, Gonzales-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19

pandemic. Lancet. 2020. Advance online publication, doi: 10.1016/S0140-6736(20)31094

https://www.covid19treatmentguidelines.nih.gov/overview/

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29. Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, Bonanomi E, D’Anitga L. An outbreak of severe Kawasaki-like

disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020. Advance online publication, doi:

10.1016/ S0140-6736(20)31129-6

30. Cavalli G, Giacomo D, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory

distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol. 2020; https://doi.org/10.1016/S2665-9913(20)30127-2

31. Mehra MR, Desai SS, Ruschitzka F, Patel AN. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-

19: a multinational registry analysis. The Lancet. 2020. DOI:https://doi.org/10.1016/S0140-6736(20)31180-6

32. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 – Preliminary Report. The New England Journal of

Medicine. 2020; doi: 10.1056/NEJMoa2007764.

Author/Owner(s): Sarah Parsons, Pharm D, BCPPS, Pharmacy Specialist, Gen Peds/CF/ID

Laura Sass MD, Peds ID

Reviewers: Eric Lowe MD, Jessica Price Pharm D, Chris Foley MD, Faiqa Qureshi, MD, Paul Mullan MD, MPH

Infectious Disease Approval: 3/20/2020

Originated: 03/20/2020 Last Revised: 06/01/2020

Revision History:03/23/20 14:45

03/30/20: updated Lopinavir/ritonavir dosing and duration, remove azithromycin from combination early initiation, added QT monitoring

recommendations and risks, NSAID statement

4/3/20: Remdesivir reference to guideline, included reference for cytokine storm

4/9/20: NG administration for hydroxychloroquine, Remdesivir added to figure 1, azithromycin changed to (+/-) in figure 1. Tables renumbered

for organization, VTE prophylaxis guidance-Reviewed by Eric Lowe MD & Jessica Price PharmD

5/4/20: Updated information on disease process in children, added EUA to remdesivir, changed to consider hydroxychloroquine to the treatment

algorithm. Added new references. Removed Lopinavir-Ritonavir

5/22:addition of definition and review of treatment for MIS-C, remdesivir EUA update, addition of chart with known indication in COVID-19 and

unclear, anakinra added to list, cytokine storm table moved to tocilizumab dosing table, QTC chart updated. MIS-C severity table, guideline for

MIS-C treatment and dosing. MIS-C flow diagram, Simplified tocilizumab dosing

5/29/20: Hydroxychloroquine removed from algorithm and ID will recommend as a 2nd line therapy if indicated, and moved to 2nd line in table 4.

ID consult added to algorithm. Reformatting of table 4

6/1/20: ID consult added to MIS-C and moderate-severe criteria combine

The recommendations in this guide are meant to serve as treatment guidelines for use at The Children’s Hospital of The King’s Daughters. As a

result of ongoing research, practice guidelines may from time to time change. The authors of these guidelines have made all attempts to ensure the

accuracy based on current information, however, due to ongoing research, users of these guidelines are strongly encouraged to confirm the

information through an independent source.

This policy is in effect for Children’s Hospital of The King’s Daughters Health System (CHKDHS) to include the following subsidiaries: Children’s

Hospital of The King’s Daughters, Incorporated (CHKD), Children’s Medical Group, Inc., and CMG of North Carolina, Inc. (CMG), and Children’s

Surgical Specialty Group, Inc. (CSSG).

https://doi.org/10.1016/S2665-9913(20)30127-2https://doi.org/10.1016/S2665-9913(20)30127-2