COVID-19
(Coronavirus disease 2019)

Abstract: COVID-19, also known as coronavirus disease 2019, is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Transmission mainly occurs via direct contact or respiratory droplets. The infection may present asymptomatically, as a mild “flu-like” illness, or severely, with shortness of breath and life-threatening complications. Individuals who are over 65 years of age, immunosuppressed, or have preexisting conditions have a higher risk of developing severe symptoms and complications. Management is based on supportive care.

Updated July 20, 2020

Coronaviruses viewed under an electron microscope. Note the characteristic crown-like (corona) appearance
Image: by CDC/ Dr. Fred Murphy, License: Public Domain Files

Table of Contents

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Table of Contents

Etiology

Coronaviruses (CoVs) are a family of enveloped, positive-sense, single-stranded RNA viruses. They tend to cause mild upper respiratory diseases in humans. Of the 7 known species of CoV, only 3 are known to cause severe infections in humans, all within the betacoronavirus genus:

  • Severe acute respiratory disease coronavirus (SARS-CoV): emerged in 2003 in southern China from civet cats
  • Middle East respiratory syndrome coronavirus (MERS-CoV): emerged in 2012 in Saudi Arabia from dromedary camels
  • SARS-CoV-2: emerged in November 2019 in China from bats (still under investigation)
    • The genome is 96.2% identical to bat coronavirus RaTG13
    • It has not yet been determined whether the virus is transmitted directly from bats or through an unknown intermediate host

Selected diseases caused by Coronaviruses

 Common coldGI tract infectionSevere acute respiratory syndrome (SARS)COVID-19 (Wuhan, China)
Incubation3 days3 days4–6 days2–14 days
IncidenceMost commonRareRareCurrent pandemic
PrognosisComplete resolutionComplete resolution
(up to 25% fatal for NEC)
30% resolution
70% severe infection
10% fatal
80% resolution
15% severe case
5% critical case
4.2% fatal (based on confirmed cases as of July 20, 2020, may change)
Clinical manifestationSneezing, rhinorrhea, headache, sore throat, malaise, fever, chillsDiarrhea, gastroenteritis, neonatal necrotizing enterocolitis

Fever > 37,8°C (100,0°F), muscle pain, lethargy, cough, sore throat, malaise

Shortness of breath/ pneumonia (direct viral or secondary bacterial)

Asymptomatic

Mild infection: fever, dry cough, malaise, dehydration

Severe infection: high fever, shortness of breath, chest pain, hemoptysis

Complications: pneumonia, ARDS, sepsis, multi-organ failure

Diseases caused by Coronaviruses

 Common ColdGI tract infection
Incubation3 days3 days
IncidenceMost commonRare
PrognosisComplete resolutionComplete resolution(up to 25% fatal for NEC)
Clinical manifestationSneezing, rhinorrhea, headache, sore throat, malaise, fever, chillsDiarrhea, gastroenteritis, neonatal necrotizing enterocolitis
 Severe acute respiratory syndrome (SARS)2019 nCoV (Wuhan City, China)
Incubation4–6 days2–14 days
IncidenceRareCurrent pandemic
Prognosis30% resolution
70% severe infection
10% fatal
80% resolution
15% severe case
5% critical case
4.2% fatal (as of July 20, 2020, based on identified cases and may change)
Clinical manifestation

Fever > 37,8°C (100,0°F), muscle pain, lethargy, cough, sore throat, malaise

Shortness of breath/ pneumonia (direct viral or sencondary bacterial)

Asymptomatic
Mild infection: fever, dry cough, muscle pain, lethargy, dehydration

Severe infection: high fever, shortness of breath, chest pain, hemoptysis

Complications: pneumonia, ARDS, sepsis, multi-organ failure

NEC: Necrotizing enterocolitis ARDS: Acute respiratory distress syndrome

The SARS-CoV-2 virion is approximately 125 nm in diameter and its genome ranges from 26–32 kb, the largest of all RNA viruses. It has 4 structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N).

  • S, E, and M proteins create the viral envelope. 
  • N protein forms a complex with RNA (nucleocapsid) and aids in the regulation of viral RNA synthesis.
  • M protein projects on the external surface of the envelope, spans the envelope 3 times, and is important in viral assembly. 
  • E protein has an unclear function, although it may aid in viral release.
  • S protein is a club-shaped surface projection, giving the virus its characteristic crown-like appearance on electron microscopy. It is responsible for receptor binding and fusion with the host cell membrane.
Structural proteins of the SARS-CoV 2 virion.
Image: by Lecturio

In January 2020, population genetic analysis concluded that SARS-CoV-2 had evolved into 2 separate genotypes:

  • L type: more aggressive and more prevalent (approximately 70% of cases in the early stages of outbreak; prevalence has since decreased) 
  • S type: evolutionary older, less common, and less aggressive (approximately 30% of cases)

     

SARS-CoV-2 attaches to the host cell by binding its S protein to the receptor protein, angiotensin-converting enzyme 2 (ACE2). ACE2 is expressed by epithelial cells of the intestine, kidney, blood vessels, and, most abundantly, in type II alveolar cells of the lungs. 

The human enzyme transmembrane protease, serine 2 (TMPRSS2), is also used by the virus for S protein priming and to aid in membrane fusion. The virus then enters the host cell via endocytosis.

SARS-CoV-2 affects the expression and presentation of ACE2, contributing to its pathogenesis in the following ways:

  • Viral entry causes internalization of the receptor, leading to its reduced availability on the cell surface. Because ACE2 is a negative regulator of the RAAS system, its downregulation directly affects cardiovascular function.
  • ACE2 inhibition induces ADAM17 gene expression, leading to the release of tumor necrosis factor α (TNFα) and cytokines such as interleukin 4 (IL-4) and interferon γ (IFNγ).
  • Increased cytokine concentrations activate further proinflammatory pathways, leading to a cytokine storm.
  • ADAM-17 also promotes the cleavage of ACE2 receptors.
  • SARS-CoV-2’s affinity for ACE2 also results in direct and acute injury to the lung, heart, endothelial cells, and, potentially, other organs.

High levels of ACE2 expression are associated with certain chronic conditions, especially cardiovascular disease, and are linked to a higher risk of severe cases of COVID-19.

The expression of ACE2 is significantly increased through the use of ACE inhibitors or angiotensin II receptor blockers (ARBs). Contrary to initial reports, the American College of Cardiology has noted that there are no data to support the claim that ACE inhibitors and ARBs increase the risk of COVID-19 infection, and recommends that patients who already use these medications should continue to do so while further studies are undertaken.

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Transmission

Coronaviruses are zoonotic; that is, they are transmitted to humans through animals. It is hypothesized that horseshoe bats are the natural reservoir of SARS-CoV-2, since the virus’s genome is 96.2% identical to that of a bat coronavirus. At this time, the intermediate host is still unknown.

Once in humans, the virus is transmitted when respiratory droplets from coughing, sneezing, or talking of infected individuals come into direct contact with the mucous membranes of another individual, including the eyes, nose, or mouth. In the air, larger droplets tend to drop toward the ground, within 1 m (3 ft) of the infected person, while smaller droplets can travel over 2 m (6 ft) and remain viable in the air for up to 3 hours under certain conditions. Other forms of transmission include the following:

  • Direct transmission through hand-to-face contact from infected surfaces
  • Fecal–oral transmission is also believed to occur (SARS-CoV-2 RNA has been detected in stool specimens, but fecal–oral transmission has not been clinically described).
  • Vertical transmission (mother-to-child) has not been reported.


COVID-19 is not considered to be airborne
, as coughing, sneezing, and talking do not generate droplets small enough to behave as aerosols. However, certain medical procedures can generate virus-laden aerosol clouds, which put healthcare personnel at a higher risk of becoming infected. (See “Prevention” for more information on aerosol-generating procedures.)

Many factors can extend the range of respiratory droplet dispersion past 2 m (6 ft). Certain actions, such as forced expiration during yelling, singing, and exercise, can increase the volume and distance that respiratory droplets can travel.

The reproductive number (R0), or the number of secondary infections generated from 1 infected individual, is 2–2.5, higher than for influenza (0.9–2.1). COVID-19 is highly contagious for the following reasons: 

  • Production of high viral loads
  • Efficient and prolonged shedding of virions from the upper respiratory tract
    • Median duration of viral RNA shedding from the upper respiratory tract is 20 days.
    • Viral shedding can outlast the resolution of symptoms.
  • Asymptomatic individuals are also infectious, posing a significant challenge for contagion prevention. 
    • Viral loads peak before symptom onset, leading to asymptomatic or presymptomatic spreading of the virus and making symptom-based detection and isolation ineffective. 
    • Asymptomatic patients can produce high viral loads in secretions of the upper respiratory tract and can shed the virus for the same amount of time as symptomatic patients.
  • SARS-CoV-2 can remain infectious on surfaces outside of a host from a few hours to a few days.
    • Viral lifespan depends on the type of surface, temperature, and humidity levels.
    • There is currently no evidence to suggest that COVID-19 can be acquired from mail and packaged goods.
Image: by Lecturio, Source: The Journal of Hospital Infection

The period of highest infectivity for symptomatic cases ranges from 2 days before the onset of symptoms up to 3 days after their resolution (exact limits are still under investigation).

Seroconversion, or the production of COVID-19-specific antibodies, occurs after 7 days in 50% of patients and by day 14 in all patients. However, it is still unclear to what degree antibodies provide a protective effect or if reinfection is possible.

Epidemiology

The first case of COVID-19 was traced back to the city of Wuhan, China, in late November 2019, with an outbreak developing in December. The virus quickly spread, with widespread ongoing transmission occurring globally. Currently, COVID-19 has been reported in every continent except Antarctica, with more than 14 million people infected and over 600,000 dead within the first 7 months of global spread. The COVID-19 outbreak was declared a Public Health Emergency of International Concern on January 30, 2020, and a pandemic on March 11, 2020, by the World Health Organization (WHO).

Coronavirus COVID-19 Global Cases by Johns Hopkins CSSE. https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6

Clinical Presentation

The incubation period for COVID-19 ranges from 2–14 days, with an average of 5 days. 

  • 80% of infections are mild or asymptomatic
  • 15% of infections are severe (requiring oxygen therapy)
  • 5% of infections are critical (requiring intensive care unit [ICU] admission and ventilation)

The proportion of severe and critical-to-mild cases is higher than in influenza infections.

The rate of severe, critical, and fatal cases varies depending on location and age group. Children are symptomatic in < 5% of cases and critical in < 1%, while up to 60% of elderly patients develop critical infections.

Asymptomatic cases:

  • These individuals can transmit the virus.
  • They represent > 50% of all infections (still under investigation).
  • They do not develop any noticeable symptoms.
  • Anosmia, hyposmia, and dysgeusia have been reported in many laboratory-confirmed cases of patients who were otherwise asymptomatic.
  • It has not been clearly determined how long asymptomatic individuals remain contagious after initial infection.
  • These individuals can present radiological and laboratory findings characteristically found in symptomatic COVID-19 patients (See “Diagnostics”.)
Mild cases:
  • May present with dry cough and moderate fever
  • Include common flu-like symptoms such as fatigue, malaise, myalgia, runny nose, nasal congestion, and sore throat
  • Less frequently experience diarrhea, nausea, vomiting, diffuse abdominal pain, productive cough, headache, and muscle or joint pain
  • Dermatologic symptoms have been reported, including maculopapular, urticarial, and vesicular eruptions, transient livedo reticularis, perniosis-like red or purple tender nodules on the distal digits (“COVID toes”)
  • Have a recovery time of approximately 2 weeks

There are no specific clinical features that can reliably distinguish COVID-19 from other viral respiratory infections such as influenza, SARS, pneumonia, or tuberculosis.

Clinical presentation of COVID-19.
Image: by Lecturio

Severe cases and complications:

  • Approximately 1 in 6 people with COVID-19 experience clinical deterioration and/or develop a complication after an average of 5–7 days.
  • Median time from onset of symptoms to the onset of critical care/ICU transfer is 8–9 days.
  • Patients develop dyspnea, high fever, chest pain, hemoptysis, anorexia, and/or respiratory crackles, which indicates the development of pneumonia (most frequent complication in severe cases).
  • Respiratory failure from acute respiratory distress syndrome (ARDS) is the most common finding in critical cases.
  • Recovery time is approximately 3–6 weeks.

Common complications of COVID-19 include interstitial pneumonia, hypoxemic respiratory failure/ARDS, acute kidney injury, and coagulopathy. Other complications include acute cardiac injury, cardiomyopathy, arrhythmia, liver dysfunction, sepsis, septic shock, and multi-organ failure.

Risk factors for a severe infection and development of complications from COVID-19 (from highest to lowest risk) include the following:

  • Age > 65 years
  • Living in a nursing home or long-term care facility
  • Chronic diseases:
    • Chronic lung disease or moderate to severe asthma
    • Cardiovascular disease
    • Immunosuppression (from long-term steroid use, cancer, AIDS/HIV infection, congenital immunodeficiency, organ transplants, immunosuppressants, etc.)
    • Severe obesity (BMI > 40)
    • Diabetes mellitus, chronic kidney disease undergoing dialysis, cerebrovascular disease, and liver disease
  • Pregnancy
    • Risk of infection is the same as in non-pregnant individuals.
    • A higher risk of severe illness in pregnant individuals is assumed due to the behavior of similar respiratory infections, such as SARS and influenza.

Refractory cases:

Nearly 50% of COVID-19 patients do not achieve clinical and radiological remission within 10 days of hospitalization. Male patients, older patients, individuals with anorexia, and those with no/low fever at the time of admission have a higher risk of presenting with a refractory progression.

COVID-19 in children

The clinical presentation and severity of cases of COVID-19 in patients < 18 years old is different from that of adults. Children are at lower risk of developing severe or critical infections, and complications appear to be milder.

In children:  
  • Approximately 55% of cases are asymptomatic or mild
  • 40% of cases are moderate (pneumonia and/or abnormal chest imaging)
  • 5% of cases are severe (dyspnea and hypoxia, requiring oxygen therapy)
  • < 1% of cases are critical (ARDS, respiratory failure, shock, or multi-organ failure requiring ICU transfer)
Pediatric inflammatory multisystem syndrome is a newly discovered complication occurring in pediatric patients. The case definition by the Royal College of Paediatrics and Child Health includes the following criteria:
  • A child presenting with persistent fever (≥ 4 days), inflammation (neutrophilia, elevated C-reactive protein, and lymphopenia) and evidence of single- or multi-organ dysfunction (shock or cardiac, respiratory, renal, gastrointestinal, or neurological disorder)
    • This may include children fulfilling full or partial criteria for Kawasaki disease.
  • Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal orstreptococcal shock syndromes, and infections associated with myocarditis (enterovirus)
  • SARS-CoV-2 PCR testing may be positive or negative.

Respiratory symptoms are only present in half of these patients. Abdominal symptoms such as pain, vomiting, or diarrhea are also common.

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Diagnostics

Reverse transcription polymerase chain reaction (RT-PCR) is currently the only test being used to confirm cases of acute COVID-19 infection and should be performed once a person under investigation (PUI) is identified according to the priorities outlined below. A positive test for SARS-CoV-2 generally confirms the diagnosis of COVID-19, regardless of the patient’s clinical status. The specimens used for testing include the following:

  • Nasopharyngeal (NP) or oropharyngeal (OP) swab
    • NP is the first choice. OP swabs are acceptable only if NP swabs are not available.
  • Nasal mid-turbinate swab or swab of anterior nares (nasal swab)
  • Nasopharyngeal wash/aspirate or nasal wash/aspirate specimen
  • Sputum (for patients with productive cough; inducing is not recommended)
  • Bronchoalveolar lavage, tracheal aspirate, pleural fluid, and lung biopsy (for patients with critical infections receiving invasive mechanical ventilation)

RT-PCR testing can be negative initially. If suspicion of COVID-19 remains, the patient should be retested every 2–3 days. In severe cases, swabs from the upper respiratory tract may be negative, while specimens from the lower respiratory tract are positive. RT-PCR tests can also yield false negatives in 20%–30% of cases. (For further information see the Centers for Disease Control and Prevention’s [CDC’s] “Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons for Coronavirus Disease 2019 (COVID-19).”)

Image: by Lecturio

1. Nasopharyngeal swab: Insert swab into a nostril parallel to the palate, and carefully slide it forward until a soft resistance is felt. Swab should reach a depth equal to distance from nostrils to outer opening of the ear. Rotate for several seconds to absorb secretions, and then slowly remove. 1. Oropharyngeal swab: Insert swab into the oral cavity without touching the gums, teeth, and tongue. A tongue depressor may be used. Swab the posterior pharyngeal wall using a rotatory motion. 2. Place swabs immediately into sterile tubes containing 2-3 ml of viral transport media. If both swabs are collected, they should be combined into a single vial. 3. Carefully leverage the swab against the tube rim to break the shaft at the scoreline. 4. Store specimens at 2-8°C for up to 72 hours after collection. If a delay in testing/shipping is expected, store specimens at -70°C or below. Use only synthetic fiber swabs with plastic shafts. Calcium alginate swabs or swabs with wooden shafts may inactivate the virus and inhibit PCR testing. 

Due to limited availability of testing in certain countries, a diagnosis of COVID-19 can be made presumptively in the presence of a compatible clinical presentation with an exposure risk, particularly when there is no other evident cause of the symptoms. Testing for other causes of respiratory illness, such as influenza, is strongly encouraged in these cases. However, a positive test result for another respiratory agent does not rule out coinfection.

During an ongoing COVID-19 outbreak, patients with suspected infection who do not present with severe symptoms are encouraged to call prior to presenting to a healthcare facility for evaluation and testing. Laboratory testing of a PUI should be prioritized as follows according to the CDC (only in a state of emergency due to shortages or limited testing capacity):

  • High priority:
    • Hospitalized patients with symptoms
    • Healthcare facility workers, workers in congregate living settings, and first responders with symptoms
    • Residents in long-term care facilities or other congregate living settings, including prisons and shelters, with symptoms
  • Priority:
    • Persons with signs and symptoms compatible with COVID-19
    • Persons without symptoms who are prioritized by health departments or clinicians for any reason, including but not limited to:
      • Public health monitoring
      • Sentinel surveillance
      • Screening of other asymptomatic individuals according to state and local plans

All PUI and confirmed cases should be reported according to the regulations stipulated by local health authorities and the national surveillance center.

Patients with COVID-19 present with the following laboratory and radiological findings. These are more pronounced and common in severe and critical cases but can also be present even in asymptomatic infections:

  • White blood cell count: leukopenia, leukocytosis, and lymphopenia (most common)
  • Inflammatory markers: ↑ LDH and ferritin
  • Liver markers: ↑ AST and ALT 
  • Chest X-ray and computed tomography (CT): 
    • Not recommended for initial evaluation; reserved for hospitalized patients or symptomatic patients with specific clinical indications
    • Common findings include ground-glass opacities (GGOs), multiple areas of consolidation, “crazy paving appearance” (GGOs + inter-/intralobular septal thickening), and bronchovascular thickening.
    • Lesions usually have a bilateral, peripheral, and lower lobe distribution.

Radiological findings associated with COVID-19 are not specific to the infection; they overlap with other respiratory illnesses including influenza, H1N1, SARS, and MERS.

In hospitalized COVID-19 patients with severe infections, regular laboratory testing and imaging are necessary for the assessment of disease progression and complications:

  • Complete blood count: Severe cases present with advanced lymphocytopenia and thrombocytopenia 
  • Arterial blood gases: to assess levels of hypoxia and acid-base balance
    • ARDS presents initially as hypoxemic respiratory failure with low PaO2 and respiratory alkalosis, later progressing into hypercapnic respiratory failure.
  • Inflammatory markers: High levels suggest immune dysregulation and progression to cytokine storm.
    • ↑ IL-6 and C-reactive protein in severe cases
    • ↑ procalcitonin in bacterial coinfection with pneumonia and/or sepsis
    • ↑ lactate in sepsis and septic shock
  • Hemostasis tests: 
    • Prolonged PT and PTT times
    • ↑ D-dimer in cardiac injury and septic shock
  • Assessment of organ function: Abnormal findings may indicate multi-organ failure
    • Creatinine, urea, and BUN used to assess renal function 
    • AST, ALT, GGT, and bilirubin used to assess hepatic function
    • Troponin and ECG used to assess cardiac function
  • Chest X-ray and CT: severe infections may also present with the following:
    • Pleural thickening and effusion
    • Lymphadenopathy
    • Air bronchograms and atelectasis
    • Solid white consolidation

Serologic testing is not recommended for acute infections. It may detect antibodies to SARS-CoV-2 in the blood of patients who have had COVID-19. The sensitivity and specificity of serologic tests is still uncertain, but preliminary studies have reported that IgM can be detected after 12 days and IgG after 14 days.

Differential Diagnoses

COVID-19InfluenzaCommon cold
Incubation period2–14 days1–4 days<3 days
OnsetGradualSuddenSudden
FeverVery commonVery commonRare
Dry coughVery common (mild to severe)Very common (mild to severe)Common (usually mild, can be productive)
FatigueCommonVery CommonRare or mild
MyalgiaCommonVery CommonMild
SneezingSometimesRare or mildVery common
Nasal congestionRare or mildCommonVery common
HeadacheSometimesVery commonRare or mild
Sore throatSometimesSometimesVery common
DiarrheaSometimesSometimesRare
DyspneaCommonRareNever

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Management

No specific treatment for COVID-19 is currently available, and no pre- or post-exposure prophylaxis is currently being used or recommended. Healthcare professionals must always implement practices for infection prevention and control when dealing with a PUI or laboratory-confirmed COVID-19 case.

All healthcare personnel and patients with confirmed or possible SARS-CoV-2 infection should wear personal protective equipment (PPE). For further information, see the CDC’s “Infection Control Guidance for Healthcare Professionals about Coronavirus (COVID-19)” and “Using Personal Protective Equipment (PPE).”

According to clinical status and laboratory and radiological findings, COVID-19 patients can be grouped into the following illness categories:

  • Asymptomatic or presymptomatic infection: individuals who test positive for SARS-CoV-2 but have no symptoms
  • Mild case: individuals who present signs and symptoms without dyspnea or abnormal imaging
  • Moderate case: individuals who have evidence of lower respiratory disease due to signs and symptoms or radiological findings, but maintain a saturation of oxygen (SaO2) > 93% on room air at sea level
  • Severe case: individuals who have a respiratory rate > 30 breaths per minute, SaO2 ≤ 93% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) < 300, or infiltrates covering > 50% of the lungs
  • Critical case: individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction
There are insufficient data to recommend the use of any antiviral or immunomodulatory therapy in patients with mild cases or asymptomatic or presymptomatic infections of COVID-19. It is recommended that these patients begin supportive at-home care. In the case of antipyretics, the use of ibuprofen is now considered safe according to the latest WHO advice (March 17, 2020). In the outpatient setting, it is important to seek professional medical assistance if any of the following emergency warning signs develop:
  • Difficulty breathing or shortness of breath
  • Persistent pain or pressure in the chest
  • Confusion or inability to arouse
  • Cyanosis (bluish tint to lips or face)

Most patients with moderate-to-severe cases of COVID-19 require hospitalization, with critical cases requiring admission to an ICU. However, the decision to monitor a patient in the inpatient setting should be made on a case-by-case basis. Once hospitalized, supportive care and acute measures should be applied as necessary, and should include the following:

  • Oxygen therapy using nasal cannula or high-flow oxygen for patients who develop respiratory distress, hypoxemia, or shock
  • Empiric antimicrobials if sepsis or secondary pneumonia is strongly suspected
  • Pharmacologic prophylaxis of venous thromboembolism
  • Corticosteroids
    • Should be avoided among patients with COVID-19 pneumonia
    • Recommended for patients who present with ARDS due to COVID-19, in the context of a clinical trial
    • Continued use is recommended for patients who are already receiving steroids for another indication, such as asthma
  • Advanced oxygen therapy, ventilatory support, and conservative fluid management in the case of ARDS or respiratory failure
  • Fluid bolus and vasopressors in the case of septic shock
  • Clinical management of other comorbidities and nosocomial complication

The mortality rate of COVID-19 varies across different countries and age groups, with a global average crude rate of 4.2%; there have been 14,348,858 cumulative cases and 603,691 deaths to date, according to the “WHO Situation Report – 182” of July 20, 2020.

The ongoing pandemic makes it difficult to determine an accurate mortality rate at this time. The rate is assumed to be lower than the current estimate due to many undetected cases (lack of widespread testing in many countries and asymptomatic individuals not seeking to be tested). Epidemiologic reports from the United States suggest the following fatality rates per age group: 10%–27% for individuals ≥ 85 years of age, 3%–11% for individuals 65–84 years of age, 1%–3% for individuals 55–64 years of age, and < 1% for individuals ≤ 54 years of age.

Causes of death in COVID-19 patients include respiratory failure, multi-organ failure, and hypotensive shock.

Investigational therapies

Several clinical trials are currently being performed to further the development and research of antiviral drugs against SARS-CoV-2. However, there are no data available as of July 20, 2020, to support the recommendation of any of the following investigational therapeutics for patients with confirmed or suspected COVID-19:

  • Remdesivir is reported to have in-vitro activity against SARS-CoV and MERS-CoV by entering nascent viral RNA chains and producing premature termination.
    • The Food and Drug Administration (FDA) issued an emergency use authorization for hospitalized children and adults with severe COVID-19.
  • Chloroquine and hydroxychloroquine, widely used antimalarial drugs, are reported to block viral entry by inhibiting virus/cell fusion.
    • The combined use of hydroxychloroquine and azithromycin, a macrolide antibiotic, was reported to reduce the detection of SARS-CoV-2 RNA in upper respiratory tract specimens. Caution is advised when administering these drugs in patients with chronic medical conditions as both are associated with QT prolongation and may lead to life-threatening arrhythmia or sudden death.
    • The FDA issued an emergency use authorization for hospitalized adolescents or adults with COVID-19 when participation in clinical trials is not feasible.
  • Convalescent plasma with a SARS-CoV-2-specific antibody (IgG) has been reported, in preliminary studies, to improve clinical status.
  • Lopinavir-ritonavir, a combined protease inhibitor usually used for HIV infection, was reported as having in-vitro inhibitory activity against SARS-CoV. However, no benefit was observed in hospitalized adult patients with severe Covid-19 in trials conducted in China.
  • Tocilizumab is an anti-IL-6 receptor agent used for rheumatoid arthritis. It is currently being investigated in patients with severe COVID-19 presenting with high IL-6 levels. 
  • Meplazumab is an anti-CD147 monoclonal antibody that has shown in-vitro inhibitory activity against SARS-CoV-2.
  • Camostat mesilate (CM), a TMPRSS2 inhibitor, is reported to block viral entry by inhibiting S protein priming.

For more information on international clinical trials, see the WHO website and clinicaltrials.gov.

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Prevention

It is now a global recommendation that all individuals should help prevent the spread of COVID-19 infection. General recommendations include the following:

  • Home isolation and quarantine: avoidance of public/crowded areas whenever possible to minimize the chance of exposure or transmission
    • Upon returning from international travel, individuals should practice home isolation for 14 days and monitor the possible onset of symptoms. 
  • Respiratory hygiene: coughs and sneezes should be covered with a tissue or the inner elbow.
  • Washing hands regularly for at least 20 seconds with soap and water or with an alcohol-based hand sanitizer that contains at least 60% alcohol
  • Social distancing: maintaining 1–2 m (approximately 3–6 ft) distance from other people
    • Certain actions, such as forced expiration during yelling, singing, and exercise, can increase the volume and distance that respiratory droplets can travel.
  • Regular cleaning of all “high-touch” surfaces within the home (see the CDC’s “Cleaning and Disinfection for Households”)
  • The use of face masks is now recommended for the general population.
    • Face masks help prevent the wearer from becoming infected and, more importantly, prevent the wearer from transmitting the disease (also known as “source control”).
    • For healthcare personnel, PPE and National Institute for Occupational Safety and Health–approved N95 disposable filtering facepiece or higher-level respirators, such as a powered air-purifying respirator, are recommended when providing care for patients with suspected or confirmed COVID-19 due to higher exposure to infected individuals as well as AGPs. AGPs include the following:
        • Open suctioning of airways
        • Sputum induction
        • Cardiopulmonary resuscitation
        • Endotracheal intubation and extubation
        • Non-invasive ventilation (eg, BiPAP, CPAP)
        • Bronchoscopy
        • Manual ventilation
    • It is still unclear how long SARS-CoV-2 can survive on human hair, but healthcare personnel is encouraged to cover hair with a disposable or surgical cap.

Isolation and quarantine can be discontinued only after the following criteria have been met:

  • At-home and hospitalized symptomatic cases: 
    • Negative results of PCR testing obtained from at least 2 consecutive nasopharyngeal swab specimens collected ≥ 24 hours apart OR
    • At least 3 days have passed since the resolution of fever without the use of antipyretics and improvement in respiratory symptoms AND
    • At least 10 days have passed since the onset of symptoms
  • Asymptomatic cases:
    • Negative results of PCR testing obtained from at least 2 consecutive nasopharyngeal swab specimens collected ≥ 24 hours apart OR
    • At least 10 days have passed since the first positive COVID-19 diagnostic test  

For further information, see the CDC’s “Healthcare Infection Prevention and Control FAQs for COVID-19.”

Vaccine

Currently, there is no FDA-approved vaccine available to prevent COVID-19. A phase 1 clinical trial evaluating an investigational vaccine began on March 16, 2020, in the Kaiser Permanente Washington Health Research Institute in Seattle, Washington. The vaccine is called mRNA-1273 and is designed to encode for a prefusion-stabilized form of the S protein. The trial will enroll 45 healthy adult volunteers aged 18–55 years over approximately 6 weeks.

The Bacille-Calmette-Guerin (BCG) vaccine, primarily used for the prevention of tuberculosis, is being evaluated for the prevention of COVID-19. Studies have reported that BCG immunization offers protection against various non-mycobacterial viruses, including herpes and influenza viruses. Clinical trials are underway to evaluate its efficiency against SARS-CoV-2.

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Additional Resources: