Definition

Coronaviruses (CoV) are a large family of single-stranded RNA viruses (+ssRNA) that cause respiratory illnesses of varying severity from a mild common cold to more severe diseases such as pneumonia. Both humans and animals are susceptible and rarely, animal coronaviruses can infect people. Viral spread occurs from person to person through close contact, for example, within a household, workplace or health care facility (long term care facility/nursing home). The most recently discovered coronavirus causes Coronavirus disease (COVID-19).

Coronaviruses are named for their appearance because of protein spikes on the surface of the virus resembles a “crown” or “corona”. Human coronaviruses were first identified nearly 60 years ago. Only seven coronaviruses are known to cause disease in humans, four of them are common and most frequently cause symptoms of the common cold but rarely can develop into lower respiratory tract infections in infants, older people, and the immunocompromised. They are:

  1. NL63 (alpha coronavirus)
  2. 229E (alpha coronavirus)
  3. OC43 (beta coronavirus)
  4. HKU1 (beta coronavirus)

The other three coronaviruses can cause severe, and sometimes fatal, respiratory infections. They are:

  1. SARS-CoV (Severe acute respiratory syndrome)
  2. MERS-CoV  (Middle East respiratory syndrome)
  3. SARS-CoV-2 (Coronavirus disease 2019, or COVID-19)


What is COVID-19?

The Coronavirus Disease 2019 or COVID-19 is the infectious disease caused by a new strain of Coronavirus family, SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), that was first discovered in 2019 and was not previously identified in humans. This strain of Coronavirus was unknown until an outbreak of respiratory illness in Wuhan, China.

Etiology

The virus can spread from person to person by respiratory droplets released when someone with the virus coughs or sneezes or exhales, hence spread can occur through

  • Close contact with an infectious person, typically within six feet of someone who is contagious
  • Touching contaminated objects or surfaces (like doorknobs or tables or phones), then touching your eyes, nose or mouth before washing your hands
  • Breathing in droplets from an infected person who coughs or exhales droplets

Currently, it is thought that COVID-19 cannot spread through the air over long distances or times and is mainly transmitted through contact with larger respiratory droplets. These droplets are too large and heavy to float in the air for longer distances and time, so they quickly land on objects and surfaces around the person who coughs or sneezes, making the area around the infected person contagious. These droplets typically spread only 1 to 2 meters; hence, current “social distancing” measures emphasize the importance of staying more than 1 to 2 meters away from others.

Survival on inert surfaces:

It is not certain how long SARS CoV-2 can survive on various surfaces, although it is generally assumed that survival varies from a few hours to several days depending on the type of surface, temperature, humidity of the environment, and some other factors. Current estimates for survival with infectious capability are:

  • In air: At least three hours
  • On plastic and stainless steel: For at least 72 hours
  • On cardboard: About 24 hours
  • On copper: Less than 4 hours

Risk Factors:

Risk factors for COVID-19 appear to include:

  • Recent travel from or residence in an area with the ongoing spread of COVID-19 as determined by Health Canada or Centers for Disease Control and Prevention (CDC) or the World Health Organization (WHO)
  • Close contact with someone who has a confirmed or probable case of COVID-19 infection
  • Elderly persons (those greater than 65 years old)
  • Compromised immune system due to:
    • Chemotherapy or radiation therapy
    • Organ or bone marrow transplant
    • Use of high doses of corticosteroids
    • HIV or AIDS infection
  • Persons who have serious chronic medical conditions including:
  • Heart disease
  • Diabetes
  • Lung disease e.g. asthma, COPD

 

Reinfection:

Until now, there are no data concerning the possibility of re-infection with SARS-CoV-2 after recovery from COVID-19, and the possibility of reinfection with SARS-CoV-2 appears very unlikely but has not been completely excluded. Viral RNA shedding declines with resolution of symptoms, and may continue for days to weeks. However, the detection of RNA during convalescence does not necessarily indicate the presence of viable infectious virus. Clinical recovery has been correlated with the detection of IgM and IgG antibodies which signal the development of immunity.

Epidemiology

Globally, more than 243 million confirmed cases of COVID-19 have been reported. The incubation period for COVID-19 infection is 1 to 14 days, with a mean of 5.2 days (95% CI 4.4 to 6.0), and most individuals (97%) develop symptoms within 10.5 days of exposure. A small proportion of cases present with acute respiratory failure, and the death rate in adults typically varies between 1% and 3%, although some countries have seen death rate above 10%.

An interactive map highlighting confirmed cases throughout the world can be found here.

Pathophysiology

The coronavirus genome encodes four major structural proteins: the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein.

  • The S protein is responsible for facilitating the entry of the Coronavirus into the target cell
  • The M protein has three transmembrane domains; defines the shape of the viral envelope and plays a central role in virus assembly
  • The E protein is a small, integral membrane protein and involved in viral pathogenesis
  • The N protein contains two domains, and it is the only protein that functions primarily to bind to the CoV RNA genome, making up the nucleocapsid

The virus has been found to use angiotensin-converting enzyme 2 (ACE2) as a functional receptor, for cell entry.

Clinical Presentation

Individuals infected with the SARS-CoV-2 virus may have little to no symptoms or maybe similar to other respiratory illnesses like flu and the common cold. Symptoms may appear 2 to 14 days after viral exposure and in most cases, it appears approximately 4 to 5 days after exposure.

Common symptoms include:

  • Fever
  • Cough, usually dry
  • Dyspnea
  • Sneezing
  • Myalgia or fatigue
  • Anorexia

Less common symptoms are:

  • Sore throat
  • Headache
  • Rhinorrhea
  • Productive cough
  • Diarrhea
  • Nausea
  • Anosmia and Dysgeusia (unexplained loss of taste or smell reported by some patients)

In children, symptoms can be:

  • Diarrhea
  • Runny nose
  • Sore throat
  • Lethargy
  • Poor feeding

Generally, people recover from this disease without needing special treatment; however, the illness can progress to a more serious condition leading to pneumonia, bronchitis, kidney failure, and even death, especially in individuals with a high risk of serious illness such as the elderly or with pre-existing medical conditions such as diabetes, heart disease or weakened immune system. The recovery time of mild COVID-19 cases appears to be around one to two weeks, and for severe disease, recovery time may go up to six weeks or more

Symptomatic individuals are advised to stay home and take the COVID-19 self-assessment and call their local Coronavirus (COVID-19) helpline or a health care provider for instructions and advice regarding testing.

Asymptomatic / pre-symptomatic:

Several studies have documented SARS-CoV-2 (COVID-19) infection in patients who never develop symptoms (asymptomatic) and in patients not yet symptomatic (pre-symptomatic) and these individuals can be a source of asymptomatic transmission.

There are two mechanisms by which asymptomatic transmission can potentially occur:

  1. Transmission from an individual who never develops symptoms i.e. if the infected person is asymptomatic throughout their infection, but nevertheless is infectious.
  2. Transmission during the incubation period i.e. if the infected person is infectious before they develop symptoms.

Hypercoagulability and COVID-19:

Some patients with COVID-19 may develop signs of a hypercoagulable state and be at increased risk for venous and arterial thrombosis of large and small vessels


Complications
:

Current information suggests that the elderly and those with chronic health conditions, particularly those with the weakened immune system, are at higher risk of developing more severe illness or complications such as:

  • Pneumonia
  • Bronchitis
  • Acute respiratory failure
  • Acute respiratory distress syndrome (ARDS)
  • Pneumonia
  • Acute cardiac injury
  • Acute kidney injury
  • Acute liver injury
  • Acute necrotizing hemorrhagic encephalopathy
  • Septic shock
  • Organ failure such as kidney failure
  • Disseminated intravascular coagulation (DIC)
  • Rhabdomyolysis
  • Death

How to Differentiate COVID-19, Flu and Cold Symptoms

How To Differentiate COVID-19, Flu And Cold Symptoms

Differential Diagnosis

Includes other etiology of respiratory tract infection.

Viral infection, e.g.:

  • Adenovirus
  • Influenza
  • Respiratory syncytial virus (RSV)
  • Parainfluenza virus
  • Human metapneumovirus (HmPV)
  • Rhinovirus (common cold)

Bacterial infection, e.g.:

  • Streptococcus pneumoniae
  • Haemophilus influenzae pneumonia
  • Moraxella catarrhalis pneumonia
  • Mycoplasma pneumoniae
  • Legionellosis

Non-infectious e.g.:

  • Pulmonary edema / Pulmonary embolism
  • COPD exacerbation / Asthma
  • ARDS / Pneumonitis
  • Acute coronary syndrome / Valvular disease
  • Congestive heart failure (CHF)

Investigation and Workup

Coronavirus (COVID-19) infection is suspected based on symptoms and diagnosis is confirmed through laboratory tests.  It is recommended and very important for everyone to self-isolate for 14 days after returning from travel outside of their country of residence and do self-assessments; if no symptoms are present then self-monitor for 14 days. If possible, assist those who require self-assessment and self-monitoring but are not able to do so by themselves.

 

Laboratory Testing:

Currently is recommended for those individuals who meet the criteria for suspected cases, and specimen for laboratory testing can be collected either from 1 site or multiple sites, depending on the diagnostic criteria, and samples to be taken are saliva (sputum), a nasal swab and/or a throat swab


Criteria for Laboratory Testing:

  • Returned from overseas in the past 14 days and you develop a respiratory illness with or without fever
  • Have been in close contact with a confirmed COVID-19 case in the past 14 days and you develop a respiratory illness with or without fever
  • Have severe community-acquired pneumonia and there is no clear cause
  • A healthcare worker who works directly with patients and you have a respiratory illness and a fever


Coronavirus (COVID-19) Diagnostic Test:

To detect the COVID-19 virus (SARS-CoV-2), there are many molecular assays have been developed or are currently under development, and many of them have been validated. A list of these assay assessment tests can be found here.


Coronavirus (COVID-19) Diagnostic Test using PCR:

SARS-CoV-2 positivity usually confirms the diagnosis of COVID-19, but there is a possibility of a false-positive test. In addition, if the tests results are negative and there is a high suspicion of SARS-CoV-2 infection, The WHO recommends resampling and testing from multiple respiratory tract sites.

  • Specimen type used in PCR:
    • Upper respiratory tract: Nasopharyngeal swab (NPS)
    • Viral throat swab (oropharyngeal swab)
    • Lower respiratory tract (when possible): sputum, bronchoalveolar lavage (BAL), bronchial wash, pleural fluid, lung tissue
    • Expectorated sputum should be collected from patients with productive cough
  • Specimen type in out-patient including ER:
    • A single upper respiratory tract specimen, either nasopharyngeal swab (NPS) or viral throat swab (oropharyngeal swab) will be accepted for COVID-19 testing
  • Specimen type in patients admitted to hospital:
    • It is recommended that both a nasopharyngeal swab (NPS) and lower respiratory tract specimens should be submitted, if possible. In addition, viral throat swab (oropharyngeal swab) and sputum, if a patient has a productive cough that can also be submitted


Rapid Coronavirus (COVID-19) Diagnostic Test:

Spartan Cube

  • On April 13th, 2020, Health Canada approved a hand-held DNA analyzer called the Spartan Cube, which is the size of a coffee cup
  • This automated test can be operated by non-laboratory personnel in settings such as airports, border crossings, doctors’ offices, pharmacies, clinics, rural, and remote communities
  • The Cube performs the test with Spartan’s COVID-19 test cartridges and proprietary swabs
  • Results can be detected in less than an hour

ID NOW COVID-19

  • The US Food and Drug Administration (FDA) has granted emergency use authorization (EUA) for a new molecular point-of-care test to detect coronavirus (COVID-19)
  • This test uses isothermal nucleic acid amplification technology
  • Positive results may be detected in as little as 5 minutes
  • Negative results in 13 minutes

Xpert Xpress SARS-CoV-2

  • The US Food and Drug Administration (FDA) has granted emergency use authorization (EUA) to detect coronavirus (COVID-19)
  • A rapid, real-time RT-PCR test intended for the qualitative detection of nucleic acid from the SARS-CoV-2
  • The test can provide rapid detection of the current pandemic coronavirus SARS-CoV-2 in approximately 45 minutes with less than a minute of hands-on time to prepare the sample
  • The modules use disposable cartridges, pre-filled with the required chemicals that are channeled around test chambers using microfluidics.


Chest CT scans and Radiographs

The Centers for Disease Control (CDC) does not currently recommend CXR or CT to diagnose COVID-19.

  • May show rounded ground-glass opacities with consolidations in the periphery of the lungs. This may also appear before symptoms are apparent
  • Generally, both lungs are involved but maybe unilateral in 25%
  • 50% of patients can have normal CT until day 2 after the onset of the symptoms
  • Some studies suggest that chest CT may be positive in the setting of a negative test
  • The World Health Organization (WHO), The Centers for Disease Control (CDC), and The Public Health Agency of Canada (PHAC) recommends
    • The diagnosis of COVID-19 infection should be confirmed by a positive RT-PCR test
    • CT should not be used to screen for, or as a first-line test to diagnose COVID-19
    • CT should reserve for hospitalized, symptomatic patients with specific clinical indications


Serological Testing:

FDA approved the serological test that looks for antibodies in the blood; results are available in 15 to 20 minutes. It is a lateral flow immunoassay intended for the qualitative detection and differentiation of IgM and IgG antibodies to SARS-CoV-2 in serum, plasma (EDTA, citrate) or venipuncture whole blood specimens.

IgM antibodies to SARS-CoV-2 are generally detectable in the blood several days after initial infection and IgG antibodies to SARS-CoV-2 become detectable later the following infection. Positive results for both IgG and IgM could occur after infection and can be indicative of acute or recent infection.


Other Laboratory findings in COVID-19:

Patient may have

    • Leukopenia, leukocytosis, and lymphopenia
    • Elevated alanine transaminase (ALT) and aspartate aminotransferase (AST)
    • Slightly elevated bilirubin levels
    • Elevated lactate dehydrogenase

Coagulation abnormalities in COVID-19:

Laboratory abnormalities commonly observed among hospitalized patients with COVID-19-associated coagulopathy include:

  • Mild thrombocytopenia
  • Increased fibrin degradation products
  • Prolonged prothrombin time
  • Increased D-dimer levels
    • Elevated D-dimer levels have been strongly associated with a greater risk of death

Treatment

The Centers for Disease Control and Prevention (CDC) new guidelines recommend that people in the US wear homemade face coverings to prevent the spread of the novel coronavirus and also advising simple cloth coverings to help people who may have the virus.

Most people with Coronavirus (COVID-19) illness have mild symptoms and recover on their own. There are currently no specific treatments for, and no available vaccine that protects against Coronavirus (COVID-19); in general, most people recover on their own. COVID-19 patients with severe infection may need oxygen therapy, and in cases of respiratory failure refractory to oxygen therapy,  they may need mechanical ventilation. Current management is directed towards isolation of patients to prevent the spread of the virus to others and supportive measures to relieve symptoms, such as:

  • Antipyretics and analgesics such as acetaminophen
  • Cough syrup or other cough medication
  • Rest
  • Maintain fluid intake
  • Humidifier or a hot shower might help with a sore throat or cough
  • Supplemental oxygen in more severe cases
  • Disinfection of frequently touched surfaces

If the patient can be treated at home, he/she may need special instructions, such as to isolate themself as much as possible from family while sick and to stay home for a period of time and wear a facemask when in the same room (or vehicle) as other people. If the patient is very ill, he/she may need to be treated in the hospital.

Note: Advice patient to get medical attention immediately if the patient or any member of the patient’s family develop emergency warning signs for Coronavirus (COVID-19) including but not limited to:

  • Difficulty breathing or shortness of breath
  • Persistent pain or pressure in the chest
  • New confusion, drowsiness, or difficulty being aroused
  • Bluish lips or face

 

MEDICATION:

There is a large-scale global effort to find various treatment options and develop vaccines for SARS-CoV2 (COVID-19).

To-date, only one medication has been approved to treat SARS-CoV2 (COVID-19).

  • Remdesivir: Recommended for use in hospitalized adults and children who are age 12 and older and who require supplemental oxygen. There is a lack of data showing benefit for patients who require mechanical ventilation

The FDA has granted an emergency use authorization (EUA) for:

  • Baricitinib: This Janus kinase (JAK) inhibitor may be used in combination with remdesivir in patients who are hospitalized and who require invasive mechanical ventilators, need supplemental oxygen, or extracorporeal membrane oxygenation (ECMO)
  • Bamlanivimab: This monoclonal antibody medication may be used to treat mild to moderate COVID-19 in people who are at high risk for disease progression due to COVID-19
  • Casirivimab and Imdevimab: Combination of these two monoclonal antibodies medications may be used to treat mild to moderate COVID-19 in people who are at high risk for disease progression due to COVID-19


VACCINES:

There are more than 145 SARS-CoV2 (COVID-19) vaccines researchers are testing, out of this about 58 clinical trials on humans and at least 87 preclinical vaccines are under active investigation in animals.

Large-scale (Phase 3) clinical trials are in progress or being planned for five SARS-CoV2 (COVID-19) vaccines in the United States:

  • Comirnaty (koe-mir’-na-tee). Also known as  Pfizer/BioNTech COVID-19 vaccine, is a genetic molecule called messenger RNA (mRNA), claiming an efficacy rate of near 95 percent. Need to store at ultra-low temperature. The vaccine triggers the body’s natural production of antibodies and stimulates immune cells to protect against COVID-19 disease and is authorized to in individuals 16 years of age or older
    • Health Canada with terms and conditions, authorized the use of the vaccine in Canada on December 9, 2020
    • The United Kingdom gave emergency authorization on December 2, 2020
    • Unites States of America: The U.S. Food and Drug Administration (FDA) approved the vaccine on August 23, 2021, to individuals 16 years of age or older. Comirnaty continues to be under Emergency Use Authorization (EUA), for individuals 12 through 15 years of age and for the administration of the third dose in certain immunocompromised individuals
    • European Union (EU): European Commission (EC) has granted a conditional marketing authorization (CMA) on December 21, 2020

Dosage:

It is a 2-dose schedule vaccine and the vaccine is given by injection (30 micrograms) into the muscle of the arm and then a second dose 21 days later.

Vaccine effectiveness in preventing SARS-CoV2 (COVID-19) infection beginning 7 days after the second dose (this means that protection is achieved 28 days after the initiation of the vaccination)

There is currently limited data available on the use of this vaccine in pregnant women. As a precaution, women avoid becoming pregnant until at least 2 months after the vaccine.

Possible side effects:

Like common side effects as of other vaccines, Pfizer/BioNTech COVID-19 vaccine’s possible side effects included pain at the site of injection, redness or swelling at the injection site, body chills, feeling tired, and feeling feverish. It’s rare but as with all vaccines, there is a chance that there will be a serious side effect.

Note: Contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation of Pfizer-BioNTech COVID-19 Vaccine, and individuals with a history of significant allergic reactions to a vaccine, medicine, or food including a previous history of anaphylactoid reactions should consult their healthcare provider for the vaccine.

  • Moderna COVID-19 vaccine: A genetic molecule called messenger RNA (mRNA), claiming an efficacy rate of near 95 percent. Need to store at low temperature. The vaccine triggers the body’s natural production of antibodies and stimulates immune cells to protect against COVID-19 disease and is authorized in individuals 18 years of age or older
    • Health Canada with terms and conditions, authorized the use of the vaccine in Canada on December 23, 2020
    • Unites States of America The U.S. Food and Drug Administration (FDA) issued Emergency Use Authorization (EUA) on December 18, 2020

Dosage:

It is a 2-dose schedule vaccine and the vaccine is given by injection (100 micrograms) into the muscle of the arm and then a second dose 28 days later.

Vaccine effectiveness in preventing COVID-19 infection beginning 14 days after the second dose.

Possible side effects:

Like common side effects as of other vaccines, the Moderna COVID-19 vaccine’s possible side effects included pain at the site of injection, redness or swelling at the injection site, body chills, feeling tired, and feeling feverish which generally goes away within a few days of appearing. It’s rare but as with all vaccines, there is a chance that there will be a serious side effect.

Note: Contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation of Moderna COVID-19 vaccine, and individuals with a history of significant allergic reactions to a vaccine, medicine, or food including a previous history of anaphylactoid reactions should consult their healthcare provider for the vaccine.

  • Oxford-AstraZeneca COVID-19 vaccine: A Viral vector vaccine, claiming an effectiveness of about 62% in preventing symptomatic COVID-19 disease. Need to store at the standard fridge, 2°C to 8°C (36°F to 46°F). The viral vector used in the Oxford-AstraZeneca COVID 19 Vaccine is based on a naturally occurring, low-prevalence chimpanzee adenovirus. It stimulates the body’s natural defences (immune system), by causing the body to produce its own protection (antibodies) against the SARS-CoV-2 virus that causes the COVID-19 infection. In this form, the vaccine cannot cause COVID 19 or adenoviral disease. The vaccine and is authorized in individuals 18 years of age or older, and there is limited information from clinical trials on the efficacy of the Oxford-AstraZeneca COVID-19 Vaccine in individuals ≥65 years of age
    • Health Canada with terms and conditions authorized the use of the vaccine in Canada on February 26, 2021
    • The European Commission: European Commission (EC) has granted a conditional marketing authorization (CMA) on January 29, 2021
    • The United Kingdom gave emergency authorization on December 30, 2020

Dosage:

It is a 2-dose, schedule vaccine, and the vaccine is given by intramuscular injection (0.5 mL) and then a second dose be administered between 4 and 12 weeks after the first dose.

Possible side effects:

Like common side effects as of other vaccines, the Oxford-AstraZeneca COVID-19 vaccine’s possible side effects included pain at the site of injection, redness or swelling at the injection site, body chills, feeling tired, and feeling feverish which generally goes away within a few days of appearing. It’s rare but as with all vaccines, there is a chance that there will be a serious side effect.

Note: Contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation of Oxford-AstraZeneca COVID-19 vaccine, and individuals with a history of significant allergic reactions to a vaccine, medicine, or food including a previous history of anaphylactoid reactions should consult their healthcare provider for the vaccine.

  • Janssen COVID-19 vaccine: A Viral vector vaccine, claiming an efficacy rate of near 67% percent against Covid-19, the vaccine was approximately 77% effective in preventing severe/critical COVID-19 occurring at least 14 days after vaccination and 85% effective in preventing severe/critical COVID-19 occurring at least 28 days after vaccination. Need to store at the standard fridge, 2°C to 8°C (36°F to 46°F). The viral vector used in the Janssen COVID‑19 Vaccine is based on a naturally occurring, low-prevalence human adenovirus. The deletion of a specific gene renders the adenovirus unable to replicate within humans, transforming it into a delivery vehicle for the genetic material encoding the spike protein of SARS-CoV-2. In this form, the vaccine cannot cause COVID‑19 or adenoviral disease. The vaccine is authorized in individuals 18 years of age or older
    • Unites States of America The U.S. Food and Drug Administration (FDA) issued Emergency Use Authorization (EUA) on February 27, 2021
    • Health Canada with terms and conditions authorized the use of the vaccine in Canada on March 5, 2021

Dosage:

It is a single dose vaccine and the vaccine is given by intramuscular injection (0.5-mL).

People had the most protection 2 weeks after getting vaccinated.

Possible side effects:

Like common side effects as of other vaccines, the Janssen COVID-19 vaccine’s possible side effects included pain at the site of injection, redness or swelling at the injection site, body chills, feeling tired, and feeling feverish which generally goes away within a few days of appearing. It’s rare but as with all vaccines, there is a chance that there will be a serious side effect.

Note: Contraindicated in individuals who are hypersensitive to the active substance or to any ingredient in the formulation of Janssen COVID-19 vaccine, and individuals with a history of significant allergic reactions to a vaccine, medicine, or food including a previous history of anaphylactoid reactions should consult their healthcare provider for the vaccine.

  • Novavax: Protein-based vaccine

There is some evidence that certain medications may have possible positive effects with regard to preventing illness or treating the symptoms of SARS-CoV2 (COVID-19) and are undergoing or will soon be studied in clinical trials before approval for use in humans.

The use of licensed medicines for indications that have not been approved by a national drug regulatory authority is considered “off-label” use.  There are several medications being used off-label in many counties by doctors for the treatment of SARS-CoV2 (COVID-19), and while the use of these medications is between the doctor and the patient it should comply with national laws and regulations.


Drugs widely discussed for SARS-CoV2 (COVID-19) treatment are:

Chloroquine (CQ) or hydroxychloroquine (HCQ)  

  • On June 15, 2020, the U.S. Food and Drug Administration (FDA) Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine. Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that chloroquine and hydroxychloroquine are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA
  • Recent results from a large randomized clinical trial in hospitalized patients, a population similar to the population for which chloroquine and hydroxychloroquine were authorized for emergency use, demonstrated that hydroxychloroquine showed no benefit on mortality or in speeding recovery

Lopinavir/ritonavir (LPV/RTV)

  • An oral antiretroviral protease inhibitor currently approved for the treatment of HIV Infection
  • In hospitalized COVID-19 patients with pneumonia, lopinavir-ritonavir (LPV/RTV) did not show any benefit and is under investigation in a World Health Organization study

Oseltamivir

  • Oseltamivir has a limited role specifically for COVID-19 and has no known effectiveness against SARS-CoV-2
  • It is prescribed because of concern of clinically similar symptoms of influenza infection

Baloxavir

  • No known activity
  • Currently no known published clinical trial data regarding efficacy or safety in the treatment of COVID-19

Favipiravir

  • Broad-spectrum antiviral with in vitro activity against various viruses, including coronaviruses
  • Only very limited clinical trial data available to date to evaluate the use of favipiravir in the treatment of COVID-19
  • Efficacy and safety of favipiravir for treatment of COVID-19 not established

Umifenovir

  • Broad-spectrum antiviral with in vitro activity against various viruses, including coronaviruses
  • There are some favorable outcomes with LPV/RTV plus umifenovir vs LPV/RTV alone in a small study conducted in China
  • Published data to support use in the treatment of COVID-19 currently are limited

Ribavirin  

  • Often proposed along with an interferon product to treat RNA viruses, in clinical trials
  • There is no known clinical trial evaluating the efficacy and safety of ribavirin in COVID-19

Tocilizumab

  • Recombinant humanized monoclonal antibody specific for the interleukin-6 (IL-6) receptor; may potentially combat cytokine release syndrome (CRS) symptoms in severely ill COVID-19 patients
  • Unpublished study from China, patients demonstrated rapid fever reduction and a reduced need for supplemental oxygen within several days

Sarilumab

  • Recombinant humanized monoclonal antibody specific for the interleukin-6 (IL-6) receptor; may potentially combat cytokine release syndrome (CRS) and pulmonary symptoms in severely ill patients
  • A randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of sarilumab in patients hospitalized with severe COVID-19 is currently underway
  • Currently, no known published clinical trial evidence supporting efficacy or safety against Coronavirus

Anakinra (anti-IL1)

  • Recombinant human interleukin-1 (IL-1) receptor antagonist; may potentially combat cytokine release syndrome (CRS) symptoms in severely ill patients
  • A randomized, open-label, multicenter trial is underway to evaluate the efficacy and safety of anakinra in patients with COVID19
  • No data to date support use in the treatment of COVID-19

Steroids

  • May prevent an extended cytokine response and may accelerate the resolution of pulmonary and systemic inflammation in pneumonia
  • May improve dysregulated immune response caused by sepsis; a possible complication of infection with COVID-19
  • Evidence suggests that cytokine storm, a hyperinflammatory state resembling secondary hemophagocytic lymphohistiocytosis (HLH), is a contributing factor in COVID-19-associated mortality
  • There are no controlled clinical trials on the use of corticosteroids in COVID-19 patients or other Coronaviruses
  • WHO and CDC recommend that steroids may be used if another compelling indication is present in patients with COVID-19 (e.g., asthma or COPD exacerbation, septic shock)

Antibiotic Therapies (ceftriaxone, azithromycin)

  • COVID-19 itself is not an indication for antibiotics
  • No data to date on in vitro activity against coronaviruses, including SARS-CoV-2
  • Concomitant antibiotic use would be to combat co-infection with a bacteria pathogen

Ascorbic acid

  • Antioxidant and cofactor for numerous physiologic reactions; may support host defenses against infection and protect host cells against infection induced oxidative stress
  • Presence of infection may decrease vitamin C concentrations

Analgesics

  • Acetaminophen is recommended as the first choice for symptomatic management of COVID-19
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
    • On March 17, the World Health Organization recommended NSAIDs should be avoided for the treatment of COVID-19 symptoms
    • The WHO reissued a statement stating that there is no specific reason to avoid NSAIDs based on current data

ACE inhibitors and ARBs

  • Human pathogenic coronaviruses bind to their target cells through angiotensin-converting enzyme 2 (ACE2)
  • Some experts believe that the expression of ACE2 in patients treated with ACE inhibitors or ARBs may worsen COVID-19 infections due to overexpression of ACE2
  • American Heart Association (AHA), American College of Cardiology (ACC), Heart Failure Society of America (HFSA), Canadian Cardiovascular Society and Hypertension Canada, and European Society of Cardiology (ESC) recommended that these agents not be discontinued in those patients who are currently prescribed such agents

Epoprostenol (inhaled)

  • Selective pulmonary vasodilator
  • May be useful in the adjunctive treatment of acute respiratory distress syndrome (ARDS), a potential complication of COVID-19
  • It can be beneficial in ARDS complication because it reduces mean pulmonary artery pressure and improve oxygenation
  • Additional studies are needed to evaluate the potential role of inhaled epoprostenol in the treatment of ARDS
  • Epoprostenol is labeled only for IV administration in the US.

Nitric oxide (inhaled)

  • Selective pulmonary vasodilator
  • May be useful in the adjunctive treatment of acute respiratory distress syndrome (ARDS), a potential complication of COVID-19
  • Inhaled nitric oxide demonstrated modest improvements in oxygenation and may be considered in patients with severe hypoxemia not responsive to conventional ventilation strategies

Convalescent plasma or serum

  • Convalescent plasma is collected from individuals who have recovered from COVID-19 infection
  • Used as a treatment in previous virus outbreaks including SARS, MERS, avian influenza, and Ebola virus infection
  • The US Food and Drug Administration (FDA) has approved the use of convalescent plasma to be used as an emergency treatment for patients with serious or immediately-life threatening COVID-19 infections
  • Severe disease is defined as:
    • Dyspnea
    • Respiratory frequency of ≥30 breaths per minute
    • Blood oxygen saturation ≤93%, ratio of the arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300
    • Lung infiltrates >50% within 24 to 48 hours
  • Life-threatening disease is defined as:
    • Respiratory failure
    • Septic shock
    • Multiple organ dysfunction or failure

Intravenous immunoglobulin (IVIG)

  • Intravenous immunoglobulin is being trialed in some patients with COVID-19
  • No clinical trial data to back use

Monoclonal antibodies (specific to SARS-CoV-2)

  • May become an alternative to convalescent plasma or serum when available

Heparins

  • Anticoagulants: Low molecular weight heparin (LMWH), Unfractionated heparin (UFH])
  • Current evidence indicates that patients with severe COVID-19 may develop a hypercoagulable state, such as
    • Thrombotic disseminated intravascular coagulation (DIC)
    • Venous thromboembolism
    • High fibrinogen levels
    • Elevated D-dimer levels
    • Microvascular thrombosis in the pulmonary vasculature
  • Data from small studies suggest that early anticoagulation in severe COVID-19 infection may improve patient outcomes and reduce thrombotic complications
  • The International Society for Thrombosis and Haemostasis (ISTH) and the American Society of Hematology (ASH) recommend that all hospitalized COVID19 patients, including non-ICU patients, should receive pharmacologic thromboprophylaxis with LMWH or fondaparinux (suggested over unfractionated heparin to reduce contact) unless contraindicated
  • Consider extended thromboprophylaxis in post-discharge patients using a regulatory-approved regimen, unless contraindicated because there is increased risk for VTE for up to 90 days after discharge in patients hospitalized for acute medical illness
  • Abnormal PT or aPTT is not a contraindication for pharmacological thromboprophylaxis

Tissue Plasminogen Activator (tPA)

  • New data from China and Italy suggest that people with severe COVID-19 infection may develop a significant blood-clotting disorder contributing to their risk of respiratory failure and acute respiratory distress syndrome (ARDS)
  • Data from a case series in COVID-19 associated Acute Respiratory Distress Syndrome (ARDS) patients suggested the use of a drug called tPA could reduce deaths among patients with ARDS as a complication of COVID-19
  • A study conducted in 2001, suggests a possible benefit for the treatment of ARDS secondary to trauma and/ or sepsis patients and were not expected to survive. These patients were treated with a plasminogen activator, and 30% of them survived following treatment
  • Additional studies are needed to evaluate the potential role of Tissue Plasminogen Activator (tPA) in the treatment of COVID-19 associated Acute Respiratory Distress Syndrome (ARDS)


Coronavirus (COVID-19) and Mental health:
(click to view and download)

This outbreak of Coronavirus (COVID-19) impacts everyone, disrupting lives, and routines around the world. It is very important during this time that while taking the preventive measures, individuals, and their family, friends, and especially their children’s mental health should not be forgotten.  The COVID-19 outbreak has led to stress, panic, fear, and increased anxiety which is understandably a natural reaction to this type of situation.

While anxiety is the natural response, functioning as an alert system that helps the person stay vigilant and respond to potential dangers, it should not escalate to interfere with daily health and wellness. Mental health stress can affect in many ways, and everyone reacts differently, such as:

  • Fear and worry about their own health and of their loved ones
  • Panic buying (e.g. toilet paper and canned goods)
  • Difficulty concentrating or sleeping
  • Changes in eating patterns
  • Frustration, irritability, or anger
  • Feeling helpless
  • Increased use of alcohol, tobacco, or other drugs

Advice patients about how to cope with stress, anxiety, or distress?

  • Person should remind themself that COVID-19 is a serious but temporary illness and that in time, life will return to normal
  • Make time to consider how to take advantage of unexpected flexibility in daily routine
  • Create a schedule for themself and their children for each day
  • Social isolation means physical distancing, stay connected with their friends and family and others by e.g. telephone, text, FaceTime, or video chatting
  • Try to engage in other activities you enjoy
  • Take breaks, hearing about the pandemic repeatedly can be upsetting
  • Avoid rumors and fake news
  • Stay connected to their official health news and recommendations for accurate information
  • Take care of their body
    • Eat healthy, well-balanced meals
    • Exercise regularly (including stretching and deep breathing exercises)
    • Get plenty of sleep
    • Mindfulness mediation might help reduce stress
    • Avoid increase use of alcohol or other drugs and smoking

Advice for parents/guardians for their children and adolescents:

  • Try not to pass anxiety on to their kids
  • Reassure their children that they are safe with the measures being undertaken to control the pandemic
  • Parents/guardians take time to talk to children about what’s happening, listen to their concerns and answer their questions realistically
  • Maintain regular routines and schedules as much as possible, or help create new ones in a new environment, including school/learning as well as time for safely playing and relaxing
  • Encourage their children to draw, write, or journal so they can express their feelings
  • Parents/guardians teach good hand-washing practices and let children know that all the adults in their lives are working hard to keep them safe
  • Give them extra love and attention

Physician Resources

1. Tips for patient care

Pets:

Advise patients to limit their interaction, and avoid direct contact with their pets and other animals, especially while they are symptomatic.

 

Strategies to reduce risk of COVID-19 infection and transmission (click to download)

Following advice is beneficial for the public to prevent themselves from COVID-19 infection.

The best way to prevent COVID-19 infection is to avoid being exposed to the virus and follow the accurate public health advice from the WHO and your local health authorities.

  • Avoid close contact with people who are ill, if possible
  • Wash hands frequently with soap and water for at least 20 seconds at a time especially after having been in a public place, or after blowing nose, coughing, or sneezing
  • Use of alcohol-based hand sanitizer containing at least 60 percent alcohol if soap and water are not available. Cover all surfaces of hands and rub them together until they feel dry
  • Avoid touching eyes, nose, and mouth with unwashed hands
  • Cover mouth and nose with a tissue, or use the inside of your elbow, when cough or sneeze
  • Avoid reuse tissue after coughing, sneezing or blowing nose, throw used tissues in a lined wastebasket and wash hands afterward
  • As much as possible keep at least 1-2 meters distance between 2 individuals except for those to whom the person is living with
  • Clean and disinfect surfaces that are frequently touched
  • Avoid all non-essential travel
  • Social distancing (physical)
  • Staying at home
  • Avoiding large public gatherings if they’re not essential
  • Minimize physical contact, especially with people at higher risk, such as elderly and people with existing health conditions
  • Avoid sharing food, dishes, glasses, bedding, and other household items if you’re sick


Steps to Protect Others

Patients and families should receive instruction to:

  • Stay home if not feeling well
  • Wear a facemask if a person is sick, especially when a person is around others (e.g. sharing a room or vehicle) and before entering a healthcare provider’s office
  • If for any valid reason person is not able to wear a facemask (e.g. trouble breathing), then do the best to cover coughs and sneezes
  • Clean and disinfect frequently touched surfaces daily e.g. tables, doorknobs, light switches, countertops, handles, desks, phones, keyboards, toilets, faucets, and sinks
  • Keep clean the surfaces by using detergent or soap and water prior to disinfection
  • Self-isolation criteria must be followed
  • Avoid having visitors to the home
  • Where possible, supplies delivered to home instead of running errands

 

Be Prepared:

Advise the person to be prepared for the COVID-19 pandemic. The virus is actively spreading everywhere around the globe and affecting almost every sector of lives and business but there is no need to be panic. Prepare for this pandemic. Familiarize yourself with self-assessment, self-monitoring tools.  Be prepared for possible self- or mandated isolation within your home for up to 14 days; ensure that you or an affected family member have enough supplies to avoid leaving your home in the event that you have to isolate or become ill. Being prepared for this outbreak can help protect your health and the health of those you care about in the event of an outbreak of COVID-19 in your community.

2. Scales and Tables

References

Core Resources:

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  • American Society of Hematology. COVID-19 and coagulopathy: frequently asked questions. From the ASH website. Accessed 2020 Apr 15. Available from https://www.hematology.org/covid19/covid-19-and-coagulopathy
  • Anderson et al, Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty, NEJM, 2018, https://www.nejm.org/doi/full/10.1056/NEJMoa1712746
  • Agostini ML, Andres EL, Sims AC et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018; 9. PubMed 29511076; DOI 10.1128/mBio.00221-18
  • Bai Y, Yao L, Wei T, et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA. 2020;323(14):1406–1407. doi:10.1001/jama.2020.2565
  • Bangash MN, Patel J, Parekh D. COVID-19 and the liver: little cause for concern. March 20, 2020; DOI:https://doi.org/10.1016/S2468-1253(20)30084-4
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  • Centers for Disease Control. Healthcare professionals: Frequently asked questions and answers. From CDC website. Accessed 2020 Apr 14. https://www.cdc.gov/coronavirus/2019-ncov/hcp/ faq.html
  • Chen L, Xiong J, Bao L. Convalescent plasma as a potential therapy for COVID-19. Volume 20, Issue 4, P398-400, April 01, 2020; DOI: https://doi.org/10.1016/S1473-3099(20)30141-9
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  • Cohen et al, Extended thromboprophylaxis with betrixaban in acutely ill medical patients. NEJM, 2019; https://www.nejm.org/doi/full/10.1056/NEJMoa1601747
  • Cortegiani A, Ingoglia G, Ippolito M et al. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care. 2020; PubMed 32173110; DOI 10.1016/ j.jcrc.2020.03.005
  • Covid-19: FDA approves use of convalescent plasma to treat critically ill patients. BMJ 2020;368:m1256
  • Deng Y, Liu W, Liu K. Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study. Chin Med J (Engl). 2020 PMID:32209890; DOI:10.1097/CM9.0000000000000824
  • Devaux CA, Rolain JM, Colson P et al. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?. Int J Antimicrob Agents. 2020; :105938. PubMed 32171740; DOI 10.1016/j. ijantimicag.2020.105938
  • de Wit E, Feldmann F, Cronin J et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020; PubMed 32054787; DOI 10.1073/pnas.1922083117
  • Farkas J. Internet Book of Critical Care. From EMCrit Project website. Accessed 2020 Apr 14. https://emcrit.org/ibcc/COVID19/
  • Fuller BM, Mohr NM, Skrupky L et al. The use of inhaled prostaglandins in patients with ARDS: a systematic review and meta-analysis. Chest. 2015; 147(6):1510-22. PMID: 25742022 DOI: 10.1378/chest.14-3161 Updated 04-17-2020
  • Keyaerts E, Vijgen L, Maes P et al. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun. 2004; 323:264-8. PubMed 15351731; DOI 10.1016/j. bbrc.2004.08.085
  • Gautret P, Lagier JC, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, International Journal of Antimicrobial Agents (2020); DOI: https://doi.org/10.1016/j.ijantimicag.2020.105949
  • Gebistorf F, Karam O, Wetterslev J et al. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016; Jun 27 (6): 1-98. PMID: 27347773 DOI: 10.1002/14651858.CD002787.pub3
  • Griffiths MJD, McAuley DF, Perkins GD et al. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Resp Res. 2019; 6:e000420. PMID 31258917 DOI: 10.1136/ bmjresp-2019-000420
  • Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). Centers for Disease Control and Prevention
  • Kirkcaldy RD, King BA, Brooks JT. COVID-19 and Postinfection ImmunityLimited Evidence, Many Remaining QuestionsJAMA. Published online May 11, 2020. doi:10.1001/jama.2020.7869
  • Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer
  • International Society of Thrombosis and Haemostasis Interim Guidance on Recognition and Management of Coagulopathy in COVID-19. From the ISTH website. Accessed 2020 Apr 15. https://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14810
  • Lamontagne F, Rochwerg B, Lytvyn L, et al. Corticosteroid therapy for sepsis: a clinical practice guideline. BMJ. 2018; 362:1-8. DOI: 10.1136/bmj.k3284. PMID: 30097460
  • Lewis SR, Pritchard MW, Thomas CM et al. Pharmacological agents for adults with acute respiratory distress syndrome (Review). Cochrane Database Syst Rev. 2019 Jul 23. DOI: 10.1002/14651858.CD004477.pub3. PMID: 31334568
  • Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection–a review of immune changes in patients with viral pneumonia. Emerging Microbes & Infections, 9:1, 727-732, DOI: 10.1080/22221751.2020.1746199
  • Mehta P, McAuley DF, Brown M et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28; 395:1033-34. PMID:32192578 DOI: 10.1016/S0140-6736 (20)30628-0
  • Retallack H, Di Lullo E, Arias C et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Natl Acad Sci U S A. 2016; 113:14408-14413. PubMed 27911847; DOI 10.1073/ pnas.1618029113
  • Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-CoV lung injury. Lancet. 2020: 395:473-5. DOI: 10.1016/S0140-6736(20)30317-2. PMID: 32043983
  • Papazian L, Aubron C, Brochard L et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019; 9(1): 69. PMID: PMID: 31197492 DOI: 10.1186/ s13613-019-0540-9
  • Searcy RJ, Morales JR, Ferreira JA et al. The role of inhaled prostacyclin in treating acute respiratory distress syndrome. Ther Adv Respir Dis. 2015; 9: 302-12. Pubmed: 26294418 DOI: 10.1177/1753465815599345
  • Sheahan TP, Sims AC, Graham RL et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017; 9. PubMed 28659436; DOI: 10.1126/ scitranslmed.aal3653
  • Tang N, Li D, Wang X. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020; 18: 844-847. PMID:32073213 DOI: 10.1111/jth.14768
  • The Canadian Association of Radiologists (CAR) and the Canadian Society. Thoracic Radiology (CSTR) Recommendations on COVID-19 Management in Imaging Departments
  • The Centers for Disease Control and Prevention (CDC. Recommendation Regarding the Use of Cloth Face Coverings, Especially in Areas of Significant Community-Based Transmission
  • The Centers for Disease Control and Prevention (CDC. Information for Clinicians on Therapeutic Options for COVID-19 Patients
  • Tran DH, Sugamata R, Hirose T et al. Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A (H1N1)pdm09 virus infection by interfering with virus internalization process. J Antibiot (Tokyo). 2019; 72:759-768. PubMed 31300721; DOI 10.1038/s41429-019-0204-x
  • S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 Apr 2. Available at https://clinicaltrials.gov.
  • Wang M, Cao R, Zhang L et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30:269-271. PubMed 32020029; DOI 10.1038/s41422- 020-0282-0
  • Wang M, Cao R, Zhang L et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30:269-271. PubMed 32020029; DOI 10.1038/s41422-020-0282-0
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  • World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance. 2020 Mar 13. From WHO website. Accessed 2020 Mar 19. https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected
  • Zhang W, Zhao Y, Zhang F et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol. 2020; 214: 108393. PMID: 32222466. DOI: 10.1016/j.clim.2020.108393.

Online Pharmacological Resources:

  • e-Therapeutics
  • Lexicomp
  • RxList
  • Epocrates

Journals/Clinical Trials:

  • Borba M, de Almeida Val F, Sousa Sampaio V, al. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study) MedRxiv 2020; DOI: https://doi.org/10.1101/2020.04.07.20056424
  • Chen L, Xiong J, Bao L. Convalescent plasma as a potential therapy for COVID-19. Volume 20, ISSUE 4, P398-400, April 01, 2020
  • Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020 Apr;92(4):418-423; DOI: 10.1002/jmv.25681
  • Kapoor KM, Kapoor A Role of Chloroquine and Hydroxychloroquine in the Treatment of COVID-19 Infection- A Systematic Literature Review. MedRxiv 2020; DOI: https://doi.org/10.1101/2020.03.24.20042366
  • Klock et al, Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research, https://www.sciencedirect.com/science/article/pii/S0049384820301201
  • Lei P, Fan B, Wang P. Differential Diagnosis for Coronavirus Disease (COVID-19): Beyond Radiologic Features. American Journal of Roentgenology: W1-W1. 10.2214/AJR.20.23119
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  • Rothana HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. https://doi.org/10.1016/j.jaut.2020.102433
  • Tian S, Hu W, Niu L et al. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer. J Thorac Oncol. 2020 Feb 28. pii: S1556-0864(20)30132-5, DOI: 10.1016/j.jtho.2020.02.010
  • Tiberghien P, de Lambalarie X, Morel P et al. Collecting and evaluating convalescent plasma for COVID-19 treatment: why and how. VOX. 2020. Epub. DOI: 10.1111/vox.12926
  • Wu C, Chen X, Cai Y. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020. PMID: 32167524; DOI:10.1001/jamainternmed.2020.0994
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  • Zhou, Z., Guo, D., Li, C. et al. Coronavirus disease 2019: initial chest CT findings. Eur Radiol (2020). https://doi.org/10.1007/s00330-020-06816-7