HOME‎ > ‎

COVID (from EMCRIT/IBCC with modifications)

Stanford Specific Information (Stanford Medicine Box required)



COVID 19 PICU Guidelines for High/Low Resource Settings (Kache S et al, Pediatric Research 2020)

Basics (from EMCRIT/IBCC with adaptations)

  • Virus is “SARS-CoV-2” and the clinical illness is called “COVID-19" (Coronavirus Disease, 2019)
  • Non-segmented, positive sense RNA virus
  • COVID-19 is part of the family of coronaviruses.  This contains:
    • (i) Four coronaviruses which are widely distributed and usually cause the common cold (but can cause viral pneumonia in patients with comorbidities).
    • (ii) SARS and MERS – these caused epidemics with high mortality which are somewhat similar to COVID-19.  COVID-19 is most closely related to SARS.
    • It binds via the angiotensin-converting enzyme 2 (ACE2) receptor located on type II alveolar cells and intestinal epithelia (Hamming 2004).
      • This is the same receptor as used by SARS (hence the technical name for the COVID-19, “SARS-CoV-2”).
      • When considering possible therapies, SARS (a.k.a. “SARS-CoV-1”) is the most closely related virus to COVID-19.
    • COVID-19 is mutating, which may complicate matters even further (figure below).  Virulence and transmission will shift over times, in ways which we cannot predict.  New evidence suggests that there are roughly two different groups of COVID-19.  This explains why initial reports from Wuhan described a higher mortality than some more recent case series (Tang et al. 2020Xu et al 2020).
      • 👁 Image showing evolution of COVID-19 here.
      • Ongoing phylogenetic mapping of new strains can be found here.



    Pathophysiology 

    • (1) ARDS
      • The primary pathology is ARDS, characterized by diffuse alveolar damage (e.g. including hyaline membranes).  Pneumocytes with viral cytopathic effect are seen, implying direct virus damage (rather than a purely hyper-inflammatory injury; Xu et al 2/17).
    • (2) Cytokine storm
      • Emerging evidence suggests that some patients may respond to COVID-19 with an exuberant “cytokine storm” reaction (with features of bacterial sepsis or hemophagocytic lymphohistiocytosis).
      • Clinical markers of this may include elevations of C-reactive protein and ferritin, which appear to track with disease severity and mortality (Ruan 3/3/20).


    Transmission

    large droplet transmission
    • COVID-19 transmission can occur via large droplet transmission (with a risk limited to ~6 feet from the patient)(Carlos del Rio 2/28).
    • This is typical for respiratory viruses such as influenza.
    • Transmission via large droplet transmission can be prevented by using a standard surgical-style mask.
    airborne transmission ??
    • It's controversial whether COVID19 can be transmitted via an airborne route (small particles which remain aloft in the air for longer periods of time).  Airborne transmission would imply the need for N95 masks (“FFP2” in Europe), rather than surgical masks.
      • Prior evidence regarding this controversy is explored further in Shiu et al 2019.
      • A recent study on COVID19 demonstrated the ability of virus to persist in aerosols for hours, making aerosol transmission plausible (Doremalen et al. 3/17/19).
    • Guidelines disagree about whether to use airborne precautions:
      • The Canadian Guidelines and World Health Organization guidelines both recommend using only droplet precautions for routine care of COVID19 patients.  However, both of these guidelines recommend airborne precautions for procedures which generate aerosols (e.g. intubation, noninvasive ventilation, CPR, bag-mask ventilation, and bronchoscopy).
      • The United States CDC recommends using airborne precautions all the time when managing COVID19 patients.
    • The type of personal protective equipment used will vary depending on availability.  Local guidelines should be followed.
    contact transmission (“fomite-to-face”)
    • This mode of transmission has a tendency to get overlooked, but it may be incredibly important.  This is how it works:
      • (i)  Someone with coronavirus coughs, emitting large droplets containing the virus.  Droplets settle on surfaces in the room, creating a thin film of coronavirus.  The virus may be shed in nasal secretions as well, which could be transmitted to the environment.
      • (ii) The virus persists on fomites in the environment.  Depending on the type of surface, virus may persist for roughly four days (Doremalen et al. 3/17/19).
      • (iii)  Someone else touches the contaminated the surface hours or days later, transferring the virus to their hands.
      • (iv)  If the hands touch a mucous membrane (eyes, nose, or mouth), this may transmit the infection.
    • Any effort to limit spread of the virus must block contact transmission.  The above chain of events can be disrupted in a variety of ways:
      • (a) Regular cleaning of environmental surfaces (e.g. using 70% ethanol or 0.5% sodium hypochlorite solutions; for details see Kampf et al 2020 and CDC guidelines).
      • (b) Hand hygiene (high concentration ethanol neutralizes the virus and is easy to perform, so this might be preferable if hands aren't visibly soiled)(Kampf 2017).
      • (c) Avoidance of touching your face.  This is nearly impossible, as we unconsciously touch our faces constantly.  The main benefit of wearing a surgical mask could be that the mask acts as a physical barrier to prevent touching the mouth or nose.
    • Any medical equipment could become contaminated with COVID-19 and potentially transfer virus to providers (e.g. stethoscope earpieces and shoes).  A recent study found widespread deposition of COVID-19 in one patient's room, but fortunately this seems to be removable by cleaning with sodium dichloroisocyanurate (Ong et al 2020).
    when can transmission occur?
    • (#1) Asymptomatic transmission (in people with no or minimal symptoms) appears to be possible (Carlos del Rio 2/28).
    • (#2) Transmission appears to occur over roughly ~8 days following the initiation of illness.
      • Patients may continue to have positive pharyngeal PCR for weeks after convalescence (Lan 2/27).  However, virus culture methods are unable to recover viable virus after ~8 days of clinical illness (Wolfel 2020).  This implies that prolonged PCR positivity probably doesn't correlate with clinical virus transmission.  However, all subjects in Wolfel et al. had mild illness, so it remains possible that prolonged transmission could occur in more severe cases.
      • CDC guidance is vague on how long patients with known COVID-19 should be isolated.  It may be advisable to obtain two paired RT-PCR tests (one of the nasopharynx and one of the pharynx), with each pair collected >24 hours apart, prior to discontinuing precautions.
    R⌀
    • R⌀ is the average number of people that an infected person transmits the virus to.
      • If R⌀ is <1, the epidemic will burn out.
      • If R⌀ = 1, then epidemic will continue at a steady pace.
      • If R⌀ >1, the epidemic will increase exponentially.
    • Current estimates put R⌀ at ~2.5-2.9 (Peng PWH et al, 2/28).  This is a bit higher than seasonal influenza.
    • R⌀ is a reflection of both the virus and also human behavior.  Interventions such as social distancing and improved hygiene will decrease R⌀.
      • Control of spread of COVID-19 in China proves that R⌀ is a modifiable number that can be reduced by effective public health interventions.
      • The R⌀ on board the Diamond Princess cruise ship was 15 – illustrating that cramped quarters with inadequate hygiene will increase R⌀ (Rocklov 2/28)


    Epidemiology


    Signs and Symptoms

    • COVID-19 may cause constitutional symptoms, upper respiratory symptoms, lower respiratory symptoms, and, less commonly, gastrointestinal symptoms.  Most patients will present with constitutional symptoms and lower respiratory symptoms (e.g. fever and cough).
      • 👁 Table of symptoms described by various studies.
    • Fever:
      • The frequency of fever is variable between studies (ranging from 43% to 98% as shown in the table above).  This may relate to exact methodology used in various studies, different levels of illness severity between various cohorts, or different strains of the virus present in various locations.  Additionally, some studies defined fever as a temperature >37.3 C (Zhou et al. 3/9/20).
      • Regardless of the exact numbers – absence of a fever does not exclude COVID-19.
    • Gastrointestinal presentations:  up to 10% of patients can present initially with gastrointestinal symptoms (e.g. diarrhea, nausea), which precede the development of fever and dyspnea (Wang et al. 2/7/20).
    • “Silent hypoxemia” – some patients may develop hypoxemia and respiratory failure without dyspnea (especially elderly)(Xie et al. 2020).
    • Physical examination is generally nonspecific.  About 2% of patients may have pharyngitis or tonsil enlargement (Guan et al 2/28).
    Typical Disease Course
    • Incubation is a median of ~4 days (interquartile range of 2-7 days), with a range up to 14 days (Carlos del Rio 2/28).
    • Typical evolution of severe disease (based on analysis of multiple studies by Arnold Forest)
      • Dyspnea ~ 6 days post exposure.
      • Admission after ~8 days post exposure.
      • ICU admission/intubation after ~10 days post exposure.  However, this timing may be variable (some patients are stable for several days after admission, but subsequently deteriorate rapidly).
    Differences in Pediatric vs. Adult Patients
    • Potentially higher co-infection rates (40% in one study of 20 pediatric patients from China) (Xia et al, Pediatric Pulmonology 2020)
    • Although generally less severe than in adults, severity of illness from a cohort of 2143 pediatric patients in China seem to demonstrate more severe (hypoxemia with SpO2 <92%) and critical (ARDS) disease in younger patients with severe/critical disease in 10.6% of those <1 year and 7.3% in those 1-5 years.
    • Tends to be less severe than in adults, with some speculation that it may be due to children lacking/having less of the ACE-II receptor the virus utilizes

    Lab Values


    complete blood count 
    • WBC count tends to be normal but can vary
    • Lymphopenia is common, seen in ~80% of patients (Guan et al 2/28Yang et al 2/21).
    • Mild thrombocytopenia is common (but platelets are rarely <100).  Lower platelet count is a poor prognostic sign (Ruan et al 3/3).
    coagulation studies
    • Coagulation labs are generally fairly normal upon admission, although elevated D-dimer is commonly seen (table above).
    • Disseminated intravascular coagulation may evolve over time, correlating with poor prognosis (figure below)(Tang et al. 2020).
      • 👁 Image of DIC labs in survivors versus non-survivors over time here.
    inflammatory markers 
    • Procalcitonin
      • COVID-19 does not appear to increase the procalcitonin.  For example, the largest series found that procalcitonin levels were <0.5 in 95% of patients (Guan et al 2/28).
      • Elevated procalcitonin may suggest an alternative diagnosis (e.g. pure bacterial pneumonia).  For patients who have been admitted with COVID-19, procalcitonin elevation may suggest a superimposed bacterial infection.
    • C-reactive protein (CRP)
      • COVID-19 increases CRP.  This seems to track with disease severity and prognosis.  In a patient with severe respiratory failure and a normal CRP, consider non-COVID etiologies (such as heart failure).
      • Young et al. 3/3 found low CRP levels in patients not requiring oxygen (mean 11 mg/L, interquartile range 1-20 mg/L) compared to patients who became hypoxemic (mean 66 mg/L, interquartile range 48-98 mg/L).
      • Ruan et al 3/3 found CRP levels to track with mortality risk (surviving patients had a median CRP of ~40 mg/L with an interquartile range of ~10-60 mg/L, whereas patients who died had a median of 125 mg/L with an interquartile range of ~60-160 mg/L)(figure below in the section on prognosis).
    evaluation for competing diagnoses
    • PCR for influenza and other respiratory viruses (e.g. RSV) may be helpful.  Detection of other respiratory viruses doesn't prove that the patient isn't co-infected with COVID-19 (~5% of patients may be co-infected with both COVID-19 and another virus)(Wang et al.).  However, an alternative explanation for the patient's symptoms will reduce the index of suspicion for COVID-19 substantially.
    • Conventional viral panels available in some hospitals will test for “coronavirus.”
      • This test does not work for COVID-19!
      • This PCR test for “coronavirus” is designed to evaluate for four coronaviruses which usually cause mild illness.
      • Ironically, a positive conventional test for “coronavirus” actually makes it less likely that the patient has COVID-19.
    • Blood cultures should be performed as per usual indications.

    IMAGING

    • Nonspecific
    • The typical finding is patchy ground glass opacities, which tend to be predominantly peripheral and basal (Shi et al 2/24).  The number of involved lung segments increases with more severe disease.  Over time, patchy ground glass opacities may coalesce into more dense consolidation.
    • Infiltrates may be subtle on chest X-ray (example above from Silverstein et al).
      • 👁 Image of example chest X-ray here.
      • 👁 Image of example CT scans here.
    • Findings which aren't commonly seen, and might argue for an alternative or superimposed diagnosis:
      • Pleural effusion is uncommon (seen in only ~5%).
      • COVID-19 doesn't appear to cause masses, cavitation, or lymphadenopathy.

    Treatment


    PPE

    LPCH Cohorting

    • PUI's requiring acute care will be cohorted in PCU 350
    • LANDING ZONE: PUI's requiring critical care (including CVICU & NICU) will be housed in our negative pressure rooms (3252, 4252) and PCU 3202-10 ("landing zone") with HEPA filters in place
      • Once these PUI's rule out for COVID, they can move to their respective unit and the general ICU population (CVICU, NICU, PICU)
      • The one exception may be SCT/Oncology patients who could potentially require a Positive Pressure Room (?)
    • PUI and COVID positive patients can be seen by trainees (Residents, fellows). However, in an effort to limit exposure as well as conserve PPE, there should be a limit of 1-2 providers (typically attending and fellow). Medical students are not allowed to see these patients.

    Overall ICU Management


    • Standard supportive treatment, similar to that of ARDS associated with influenza (without the oseltamivir)
      • Lung protective ventilation (IBW ~6 cc/kg) utilizing open lung strategy
      • Permissive Hypercapnea (pH > 7.15 to avoid injurious ventilator settings) 
      • Attention to fluid overload with diuresis as needed for negative fluid trajectory
      • Consider prone positioning
      • Monitoring for evidence of co-infection
      • Enteral nutrition as able
      • Standard sedation
    • Potential Exceptions:
      • Myocarditis: Some reports of severe cardiomyoapthy associated with myocarditis like picture (consider obtaining troponins), consider IVIG if myocarditis diagnosed. 
      • Antivirals: Currently no evidence in humans that antivirals are effective and generally are being given within trials/compassionate use basis
      • Steroids: 
        • Currently, CDC and WHO recommend AGAINST use of steroids in COVID, with concerns that it is associated with increased mortality (influenza) or prolong viral shedding (MERS). 
        • However, it may potentially be helpful in COVID-19 related ARDS, although very limited data (and some concerns of increased viral shedding with other viruses): 
        • Wu et al 3/13/20 JAMA
          • Retrospective single-center study describing 201 patients with COVID-19 pneumonia.
          • Improved mortality in patients treated with methylprednisolone (HR 0.38, 0.2-0.72)
          • Typically steroid is used in the sickest patients, so this will create a bias towards seeing worse outcomes in patients treated with steroid.  A correlation in the opposite direction is surprising, and suggests that steroid could be causing benefit.
        • There is a potential use of low-dose corticosteroid in patients with ARDS and elevated inflammatory markers (e.g. C-reactive protein).
        • Regimens used in China were typically methylprednisolone 40-80 mg IV daily for a course of 3-6 days

    Antivirals/Immunomodulators


        Remdesivir
    • Remdesivir might be an excellent antiviral, based on a study involving in vitro and animal data with MERS (e.g. Sheahan 2020).
    • Unfortunately, remdesivir is not commercially available.  Remdesivir was used on the basis of “compassionate use” for one of the first patients with COVID-19 in the United States (Holshue 2020).
    • Remdesivir is being used in one trial in the United States being sponsored by NIAID.  Enrollment in this trial is the most desirable approach to antiviral therapy (if feasible)
        Chloroquine/Hydrochloroquine
       Tocilizumab
    • Tocilizumab is a recombinant humanized monoclonal antibody which binds to the interleukin-6 (IL-6) receptor and blocks it from functioning.
    • Tocilizumab is most commonly used to treat rheumatoid arthritis.  It may also be used to treat cytokine release syndrome following CAR-T therapy.
    • Mechanistically, tocilizumab would be expected to benefit patients with COVID-19 who develop a cytokine storm (which involves elevated levels of IL-6, a major pro-inflammatory cytokine)
    • No high-level evidence is currently available.
    • Tocilizumab been used in Italy (podcast discussions regarding this here and here).
    • Case series from China (Xu et al.)
      • 21 hypoxemic patients were treated with tociliumab 400 mg as an intravenous infusion (most patients received a single dose, but 3 patients received two doses).
      • Patients appeared to improve clinically, with rapid reduction in inflammatory markers.  No adverse effects were noted
        Convalescent Serum

    Intubation

    • LPCH PUI/COVID Airway Management Guidelines (Stanford Medicine Box Required)
    • This represents a high risk for transmission to healthcare workers
    • Given potentially more acute worsening with COVID, consider earlier NPO/IVF and standardized check-in with ICU team of PUI/COVID patients on acute care upon admission/with each shift
        Indications
    • Early intubation and avoidance of HFNC and NIPPV being advocated for adult patients given the potential risk of aerosolization and thus health care worker risk with non-invasive ventilation
    • Given different prevalence of COVID-related critical illness in pediatric patients (vs. critical-illness from other respiratory pathogens such as influenza, RSV, etc), there will likely be more use of HFNC and NIPPV in pediatric patients, particularly PUI's (patients under investigation). Adhering to isolation protocols and proper donning/doffing of PPE will be important. Similarly, such patients should be placed in negative pressure/HEPA filtered rooms.
    • Rough guideline for HFNC: No more than 2 LPM/kg flow, 50% FiO2 before escalation to either CPAP/BiPAP or endotracheal intubation
    • Rough Guideline for NIPPV: Max BiPAP of 16/10 40% for <4 hours--> patients should demonstrate improvement as noted by improved RR, WOB, O2 saturations (93%+) or otherwise should proceed to intubation
    • SpO2 <92%, pCO2 >50, pH <7.3 despite above support
        Process 
    • All intubations should occur in negative pressure rooms (? HEPA filtered rooms)- this includes patients who need to go to the OR, who should be intubated prior to going to the OR
    • Organize medications (ideally rapid sequence intubation-RSI, minimizing bag mask ventilation)
    • Bag-valve-mask with viral filter in place
    • Personnel: 
      • 1-2 MD (PICU/NICU/CVICU/Anesthesia Attending/Fellow), 1 RN, 1 RT. 
      • Also consider having 1-2 RT/RN's outside the room to gather any other necessary equipment, help troubleshoot.
      • Consider early call to difficult airway team for standby backup should there be any concern about the patient's airway to avoid multiple attempts
    • Don appropriate PPE (CAPR, gown, gloves, face shield/goggles)
    • Only experienced (attending/fellow) operator should intubate
    • Utilize video laryngoscopy and screen (CMAC or Glidescope) in lieu of direct visualization to minimize exposure
    • RSI with minimal BVM as able
    • PediCAP (qualitative ETCO2 detector) or ETCO2 behind viral filter on bag should be used to confirm ETT placement


    ECMO

    • Could be utilized for PUI/COVID patients with respiratory (VV) or cardiopulmonary (VA) failure
    • At this time, ECPR is not recommended for our PUI/COVID patients

    References/Resources:

    OVERVIEWS:

    1. UpToDate: COVID

    2. CDC Coronavirus page: symptoms, community resources, US case tracker, info for providers, latest updates
    https://www.cdc.gov/coronavirus/2019-ncov/index.html

    3. EM Crit: Excellent overview, includes diagnosis and treatment, discusses meds
    https://emcrit.org/ibcc/covid19/

    4. EB Medicine: Excellent overview, epidemiology, ER and Hospitalist management, “situation summary”, PDF to print
    https://www.ebmedicine.net/topi…/infectious-disease/COVID-19

    5. Seattle Intensivist One-Page Summary on Covid-19, excellent visual
    https://www.kevinmd.com/…/an-intensivists-one-pager-on-covi…

    6. MIT's COVID Resources

    Pediatric Specific Papers

    1) Epidemiology of COVID (Chinese experience) Dong et al, Pediatrics 2020

    2) Pediatric Patients with COVID (China, 20 patients) Xia et al, Pediatric Pulmonology 2020

    3) 6 Patients with COVID, Liu et al, NEJM 2020

    Protocols
    1. UW
    https://covid-19.uwmedicine.org/

    2. UCSF
    https://infectioncontrol.ucsfmedicalcenter.org/coronavirus

    TRACKERS
    1. WHO Daily Situation Reports
    https://www.who.int/…/novel-coronavirus-2…/situation-reports

    2. North America Tracker
    https://coronavirus.1point3acres.com/

    3. Johns Hopkins Tracker
    https://coronavirus.jhu.edu/map.html

    FOREIGN LANGUAGE RESOURCES
    1. NYC GOV, scroll down to “Posters”
    https://www1.nyc.gov/…/health/health-topics/coronavirus.page

    2. Use of Single Ventilator for Multiple Patients
    http://rc.rcjournal.com/content/57/3/399

    3. ECMO: Halfway down page are links on scientific literature/management
    https://www.elso.org/covid19

    OBSTETRICS
    1. ACOG Practice Advisory (MOST UP TO DATE LINKS to almost all topics!
    https://www.acog.org/…/Practice-Advisory-Novel-Coronavirus2…

    3. CDC Pregnancy and Breastfeeding
    https://www.cdc.gov/…/…/prepare/pregnancy-breastfeeding.html

    4. CDC COCA Webinar on Pregnanct and Pediatrics (summarized in post labeled OB/PEDIATRICS), audio resource
    https://emergency.cdc.gov/c…/calls/2020/callinfo_031220.asp…

    5. ACOG Outpatient Assessment of Pregnant Women with COVID-19
    https://www.acog.org/…/Practice-Adv…/COVID-19-Algorithm5.pdf

    6. CDC and ACOG Infection Prevention and Control in Inpatient Settings
    https://www.cdc.gov/…/inpatient-obstetric-healthcare-guidan…

    OUTPATIENT / URGENT CARE PROTOCOLS
    1. See Master Protocol Sites above
    2. AAFP Response
    https://www.aafp.org/patien…/emergency/2019-coronavirus.html

    2. AAP Early COVID-19 Data/Pedi Epidemiology
    https://pediatrics.aappublications.org/…/peds.2020-0702.ful…

    3. Clinical and CT Differences Between Peds and Adults w COVID-19
    https://onlinelibrary.wiley.com/doi/10.1002/ppul.24718

    RADIOLOGY
    1. Society of Italian Radiology: multiple cases of CXR and CT scans
    https://www.sirm.org/category/senza-categoria/covid-19

    2. Lung US Findings
    https://link.springer.com/article/10.1007/s00134-020-05996-6

    2. ACS Statement on Elective Procedures
    https://www.facs.org/abou…/covid-19/information-for-surgeons

    3. Surgical Grand Rounds Discussion, video
    https://www.youtube.com/watch…

    4. Preparing OR for Emergent Case
    https://link.springer.com/epdf

    SPECIALTY SPECIFIC

    1. Cardiology
    ---- Statement from ACC: https://www.acc.org/~/…/665AFA1E710B4B3293138D14BE8D1213.pdf

    ----ACC Statement on Rapid Implementation of Telehealth in Cards Clinic
    https://www.acc.org/…/feature-telehealth-rapid-implementati…

    2. Endocrinology
    ---- T1DM FAQ and Supply Chain
    https://www.jdrf.org/coronavirus

    3. Gastroenterology
    ---- Joint Statement from AGA, ACG, AASLD, ASGE
    https://www.gastro.org/…/joint-gi-society-message-covid-19-…

    ---- ASGE Statement on Endoscopy Precautions
    https://els-jbs-prod-cdn.literatumonline.com/…/CoronavirusO…

    4. Jails / Inmates
    ---- Federal Bureau of Prisons Action Plan
    https://www.bop.gov/mobile/

    ---- Statement from King County
    https://www.kingcounty.gov/depts/jails.aspx

    5. Ophthalmology
    ---- AAO Statement
    https://www.aao.org/hea…/alert-important-coronavirus-context

    6. Psychiatry / Mental Health
    ---- Resources for Psychiatrists: excellent! Discusses telehealth, PPE, etc.!
    https://www.psychiatry.org/…/covid-19-mental-health-impacts…

    TELEMEDICINE

    1. AAP Coding and Billing Factsheet https://www.aap.org/…/Doc…/coding_factsheet_telemedicine.pdf

    2. AAP Telemedicine Resources https://www.aap.org/…/ma…/telehealth-care/Pages/default.aspx

    3. See specialty specific tabs for more resources on: cardiology

    TREATMENT ARTICLES

    1. ACEI / ARBS
    http://www.nephjc.com/news/covidace2
    https://www.ncbi.nlm.nih.gov/m/pubmed/32129518
    https://www.escardio.org/…/position-statement-of-the-esc-co…

    2. Chloroquine
    https://www.jstage.jst.go.jp/…/adv…/0/advpub_2020.01047/_pdf

    3. Remdesivir and Chloroquine
    https://www.nature.com/articles/s41422-020-0282-0

    4. Favilavir
    https://www.pharmaceutical-technology.com/…/china-approves-…

    EXAMPLES OF FIRST-HAND ACCOUNTS
    1. Wuhan
    https://www.sciencedirect.com/…/artic…/pii/S0140673620301835

    2. Harvard’s Study of over 25,000 Cases in China
    https://drive.google.com/…/14tGJF9tdv4osPhY1-fswLcSlWZJ9zx45

    3. Italy: Jama Network
    https://edhub.ama-assn.org/jn-learning/video-player/18315311